Vanilloid receptor ligands and their use in treatments

ABSTRACT

Compounds having the general structure 
                         
and compositions containing them, for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.

This application is a division of application Ser. No. 10/638,009, filedAug. 8, 2003, now U.S. Pat. No. 7,144,888, which claims benefit of USProvisional Application No. 60/402,422, filed Aug. 8, 2002, which arehereby incorporated by reference.

BACKGROUND

The vanilloid receptor 1 (VR1) is the molecular target of capsaicin, theactive ingredient in hot peppers. Julius et al. reported the molecularcloning of VR1 (Caterina et al., 1997). VR1 is a non-selective cationchannel which is activated or sensitized by a series of differentstimuli including capsaicin and resiniferatoxin (exogenous activators),heat & acid stimulation and products of lipid bilayer metabolism,anandamide (Premkumar et al., 2000, Szabo 75 et al., 2000, Gauldie etal., 2001, Olah et al., 2001) and lipoxygenase metabolites (Hwang etal., 2000). VR1 is highly expressed in primary sensory neurons (Caterinaet al., 1997) in rats, mice and humans (Onozawa et al., 2000, Mezey etal., 2000, Helliwell et al., 1998, Cortright et al., 2001). Thesesensory neurons innervate many visceral organs including the dermis,bones, bladder, gastrointestinal tract and lungs; VR1 is also expressedin other neuronal and non-neuronal tissues including but not limited to,CNS nuclei, kidney, stomach and T-cells (Nozawa et al., 2001, Yiangou etal., 2001, Birder et al., 2001). Presumably expression in these variouscells and organs may contribute to their basic properties such ascellular signaling and cell division.

Prior to the molecular cloning of VR1, experimentation with capsaicinindicated the presence of a capsaicin sensitive receptor, which couldincrease the activity of sensory neurons in humans, rats and mice(Holzer, 1991; Dray, 1992, Szallasi and Blumberg 1996, 1999). Theresults of acute activation by capsaicin in humans was pain at injectionsite and in other species increased behavioral sensitivity to sensorystimuli (Szallasi and Blumberg, 1999). Capsaicin application to the skinin humans causes a painful reaction characterized not only by theperception of heat and pain at the site of administration but also by awider area of hyperalgesia and allodynia, two characteristic symptoms ofthe human condition of neuropathic pain (Holzer, 1991). Taken together,it seems likely that increased activity of VR1 plays a significant rolein the establishment and maintenance of pain conditions. Topical orintradermal injection of capsaicin has also been shown to producelocalized vasodilation and edema production (Szallasi and Blumberg 1999,—Singh et al., 2001). This evidence indicates that capsaicin throughit's activation of VR1 can regulate afferent and efferent function ofsensory nerves. Sensory nerve involvement in diseases could therefore bemodified by molecules which effect the function of the vanilloidreceptor to increase or decrease the activity of sensory nerves.

VR1 gene knockout mice have been shown to have reduced sensorysensitivity to thermal and acid stimuli (Caterina et al., 2000)). Thissupports the concept that VR1 contributes not only to generation of painresponses (i.e. via thermal, acid or capsaicin stimuli) but also to themaintenance of basal activity of sensory nerves. This evidence agreeswith studies demonstrating capsaicin sensitive nerve involvement indisease. Primary sensory nerves in humans and other species can be madeinactive by continued capsaicin stimulation. This paradigm causesreceptor activation induced desensitization of the primary sensorynerve—such reduction in sensory nerve activity in vivo makes subjectsless sensitive to subsequent painful stimuli. In this regard bothcapsaicin and resinferatoxin (exogenous activators of VR1), producedesensitization and they have been used for many proof of conceptstudies in in vivo models of disease (Holzer, 1991, Dray 1992, Szallasiand Blumberg 1999).

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SUMMARY

The present invention comprises a new class of compounds useful in thetreatment of diseases, such as vanilloid-receptor-mediated diseases andother maladies, such as inflammatory or neuropathic pain and diseasesinvolving sensory nerve function such as asthma, rheumatoid arthritis,osteoarthritis, inflammatory bowel disorders, urinary incontinence,migraine and psoriasis. In particular, the compounds of the inventionare useful for the treatment of acute, inflammatory and neuropathicpain, dental pain, general headache, migraine, cluster headache,mixed-vascular and non-vascular syndromes, tension headache, generalinflammation, arthritis, rheumatic diseases, osteoarthritis,inflammatory bowel disorders, inflammatory eye disorders, inflammatoryor unstable bladder disorders, psoriasis, skin complaints withinflammatory components, chronic inflammatory conditions, inflammatorypain and associated hyperalgesia and allodynia, neuropathic pain andassociated hyperalgesia and allodynia, diabetic neuropathy pain,causalgia, sympathetically maintained pain, deafferentation syndromes,asthma, epithelial tissue damage or dysfunction, herpes simplex,disturbances of visceral motility at respiratory, genitourinary,gastrointestinal or vascular regions, wounds, burns, allergic skinreactions, pruritus, vitiligo, general gastrointestinal disorders,gastric ulceration, duodenal ulcers, diarrhea, gastric lesions inducedby necrotising agents, hair growth, vasomotor or allergic rhinitis,bronchial disorders or bladder disorders. Accordingly, the inventionalso comprises pharmaceutical compositions comprising the compounds,methods for the treatment of vanilloid-receptor-mediated diseases, suchas inflammatory or neuropathic pain, asthma, rheumatoid arthritis,osteoarthritis, inflammatory bowel disorders, urinary incontinence,migraine and psoriasis diseases, using the compounds and compositions ofthe invention, and intermediates and processes useful for thepreparation of the compounds of the invention.

The compounds of the invention are represented by the following generalstructure:

or a pharmaceutically acceptable salt thereof, wherein J, R¹, R⁴, R^(d),X and Y are defined below.

The foregoing merely summarizes certain aspects of the invention and isnot intended, nor should it be construed, as limiting the invention inany way. All patents, patent applications and other publications recitedherein are hereby incorporated by reference in their entirety.

DETAILED DESCRIPTION

One aspect of the current invention relates to compounds having thegeneral structure:

or any pharmaceutically-acceptable salt thereof, wherein:

-   -   J is O or S;    -   X is N or ═C(R²);    -   Y is N or ═C(R³), wherein at least one of X and Y is not N;    -   n is independently, at each instance, 0, 1 or 2.

R¹ is

or R¹ is R^(b) substituted by 1, 2 or 3 substituents independentlyselected from R^(f),R^(g), halo, nitro, cyano, —OR^(e), —OR^(g), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and R^(b) is additionally substituted by 0, 1 or 2groups independently selected from R^(c); or R¹ is phenyl that isvicinally fused with a saturated or unsaturated 3-, 4- or 5-atom bridgecontaining 0, 1, 2 or 3 atoms selected from O, N and S with theremaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2, wherein the heterocycle and bridge aresubstituted by 0, 1, 2 or 3 substituents independently selected from R⁵;

R² is, independently, in each instance, R¹⁴, halo, C₁₋₈alkyl substitutedby 0, 1 or 2 substituents selected from R¹⁴, halo, —(CH₂)_(n)phenylsubstituted by 0, 1, 2 or 3 substituents independently selected from R¹⁴and halo, or a saturated or unsaturated 5- or 6-membered ringheterocycle containing 1, 2 or 3 heteroatoms independently selected fromN, O and S, wherein no more than 2 of the ring members are O or S,wherein the heterocycle is optionally fused with a phenyl ring, and theheterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3substituents independently selected from R¹⁴ and halo; or R² is —OR⁴ or—N(R^(a))R⁴;

R³ is, independently, in each instance, H, halo, —NH₂, —NHC₁₋₃alkyl,—N(C₁₋₃alkyl)C₁₋₃alkyl, or C₁₋₃alkyl; wherein, when X is C(R²) and Y isC(R³) then at least one of R² and R³ is other than H;

R⁴ is independently at each instance

R⁴ is independently at each instance a saturated or unsaturated 5- or6-membered ring heterocycle containing 1, 2 or 3 atoms selected from O,N and S that is optionally vicinally fused with a saturated orunsaturated 3-, 4- or 5-atom bridge containing 0, 1, 2 or 3 atomsselected from O, N and S with the remaining atoms being carbon, so longas the combination of O and S atoms is not greater than 2, wherein theheterocycle and bridge are substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(e), C₁₋₄haloalkyl, halo, cyano, oxo,thioxo, —OR^(f), —S(═O)_(n)R^(e), —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —OC₁₋₆alkylC(═O)OR^(e),—NR^(a)R^(f), —NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(e), —C(═O)OR^(f), —OC(═O)R^(e),—C(═O)NR^(a)R^(f) and —NR^(a)C(═O)R^(e); or R⁴ is independently at eachinstance naphthyl substituted by 1, 2 or 3 substituents independentlyselected from C₁₋₄haloalkyl, halo, nitro, cyano, —S(═O)_(n)R^(e),—OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—OC₁₋₆alkylC(═O)OR^(e), —NR^(a)C₁₋₄haloalkyl,—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(e),—C(═O)OR^(f), —OC(═O)R^(e) and —C(═O)NR^(a)R^(f); but in no instance isR⁴-phenyl-(C₁₋₈alkyl), -phenyl-O-(C₁₋₆alkyl), -phenyl-NR^(a)R^(a) or-phenyl-N(R^(a))C(═O)(C₁₋₈alkyl);

R⁵ is independently, at each instance, R^(f), R^(h), halo, nitro, cyano,—OR^(f), —OR^(h), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—NR^(a)R^(f), —NR^(a)R^(h), —NR^(f)C₂₋₆alkylNR^(a)R^(f),—NR^(f)C₂₋₆alkylOR^(f), naphthyl, —CO₂R^(e), —C(═O)R^(e), —OC(═O)R^(e),—C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(h), —NR^(f)C(═O)R^(e),—NR^(f)C(═O)R^(h), —NR^(f)C(═O)NR^(a)R^(f), —NR^(f)CO₂R^(e),—C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e),—S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e), —OS(═O)₂R^(e),—OC(═O)NR^(a)R^(f), —OR^(h), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—NR^(a)R^(h), —NR^(f)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylN^(a)R^(f),—NR^(h)C₂₋₆alkylOR^(f), —NR^(f)C₂₋₆alkylOR^(h), —CO₂R^(h), —OC(═O)R^(h),—C(═O)R^(h), —C(═O)NR^(a)R^(h), —NR^(f)C(═O)R^(h), —NR^(h)C(═O)R^(f),—NR^(h)C(═O)NR^(a)R^(f), —NR^(f)C(═O)NR^(a)R^(e), —NR^(h)CO₂R^(h),—NR^(f)CO₂R^(h), —C₁₋₈alkylOR^(h), —C₁₋₆alkylNR^(a)R^(h),—S(═O)_(n)R^(h), —S(═O)₂NR^(a)R^(h), —NR^(a)S(═O)₂R^(h),—NR^(h)S(═O)₂R^(e), —OS(═O)₂R^(h) or —OC(═O)NR^(a)R^(h);

R⁶ is independently, at each instance, H, C₁₋₅alkyl, C₁₋₄haloalkyl,halo, nitro —OR^(e), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—NR^(a)R^(a), —NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a) or—NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a),—S(C₁₋₆alkyl), a phenyl ring substituted with 1, 2, or 3 substituentsindependently selected from R¹⁴ and halo; or R⁶ is a saturated orunsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atomsselected from O, N and S substituted with 0, 1, 2, or 3 substituentsindependently selected from R¹⁴ and halo;

R⁷ is independently, at each instance, H, C₁₋₈alkyl, C₁₋₄haloalkyl,halo, cyano, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆a OR^(a), —NR^(a)R^(a), —NR^(a)C₁₋₄haloalkyl,—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a),—C₁₋₆alkylNR^(a)R^(a) or —S(C₁₋₆alkyl); or R⁷ is a saturated orunsaturated 4- or 5-membered ring heterocycle containing a singlenitrogen atom, wherein the ring is substituted with 0, 1 or 2substituents independently selected from halo, C₁₋₂haloalkyl andC₁₋₃alkyl;

R⁸ is independently, at each instance, H, C₁₋₅alkyl, C₁₋₄haloalkyl,halo, nitro, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —NR^(a)R^(a), —NR^(a)C₁₋₄haloalkyl,—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₁₋₈akylOR^(a),—C₁₋₆alkylNR^(a)R^(a), —S(C₁₋₆alkyl), a phenyl ring substituted with 1,2, or 3 substituents independently selected from R¹⁴ and halo, or R⁸ isa saturated or unsaturated 5- or 6-membered ring heterocycle containing1, 2 or 3 atoms selected from O, N and S substituted with 0, 1, 2, or 3substituents independently selected from R¹⁴ and halo;

R⁹ is independently, at each instance, R^(f), R^(h), halo, nitro, cyano,—OR^(f), —OR^(h), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—NR^(a)R^(f), —NR^(a)R^(h), —NR^(f)C₂₋₆alkylNR^(a)R^(f),—NR^(f)C₂₋₆alkylOR^(f), naphthyl, —CO₂R^(e), —OC(═O)R^(e), —C(═O)R^(e),—C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(h), —NR^(f)C(═O)R^(e),—NR^(f)C(═O)R^(h), —NR^(f)C(═O)NR^(a)R^(f), —NR^(f)CO₂R^(e),—C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e),—S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e), —OS(═O)₂R^(e),—OC(═O)NR^(a)R^(f), —OR^(h), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—NR^(a)R^(h), —NR^(f)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(h)C₂₋₆alkylOR^(f), —NR^(f)C₂₋₆alkylOR^(h), —CO₂R^(h), —OC(═O)R^(h),—C(═O)R^(h), C(═O)NR^(a)R^(h), —NR^(f)C(═O)R^(h), —NR^(h)C(═O)R^(f),—NR^(h)C(═O)NR^(a)R^(f), —NR^(f)C(═O)NR^(a)R^(h), —NR^(h)CO₂R^(e),—NR^(f)CO₂R^(h), —C₁₋₈alkylOR^(h), —C₁₋₆alkylNR^(a)R^(h),—S(═O)_(n)R^(h), —S(═O)₂NR^(a)R^(h), —NR^(a)S(═O)₂R^(h),—NR^(h)S(═O)₂R^(e), —OS(═O)₂R^(h) or —OC(═O)NR^(a)R^(h); or R⁹ is asaturated or unsaturated 4- or 5-membered ring heterocycle containing asingle nitrogen atom, wherein the ring is substituted with 0, 1 or 2substituents independently selected from halo, C₁₋₂haloalkyl andC₁₋₃alkyl;

wherein at least one of R⁵, R⁶, R⁷, R⁸ and R⁹ is R^(e), R^(h), halo,nitro, cyano, —OR^(h), —NR^(a)R^(f), —NR^(a)R^(h),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —OC(═O)R^(e), —C(═O)NR^(a)R^(f),—C(═O)NR^(a)R^(h), —NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(h),—NR^(f)C(═O)NR^(a)R^(f), —NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f),—C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f),—NR^(a)S(═O)₂R^(e), —OS(═O)₂R^(e), —OC(═O)NR^(a)R^(f), —OR^(h),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —NR^(a)R^(h),—NR^(f)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(h)C₂₋₆alkylOR^(f), —NR^(f)C₂₋₆alkylOR^(h), —CO₂R^(h), —OC(═O)R^(h),—C(═O)R^(h), —C(═O)NR^(a)R^(h), —NR^(f)C(═O)R^(h), —NR^(h)C(═O)R^(f),—NR^(h)C(═O)NR^(a)R^(f), —NR^(f)C(═O)NR^(a)R^(h), —NR^(h)CO₂R^(e),—NR^(f)CO₂R^(h), —C₁₋₈alkylOR^(h), —C₁₋₆alkylNR^(a)R^(h),—S(═O)_(n)R^(h), —S(═O)₂NR^(a)R^(h), —NR^(a)S(═O)₂R^(h),—NR^(h)S(═O)₂R^(e), —OS(═O)₂R^(h), —OC(═O)NR^(a)R^(h), or —OC₁₋₈alkylsubstituted by 1, 2 or 3 substituents independently selected from R^(f),R^(h), halo, nitro, cyano, —OR^(f), —OR^(h), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(h),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —OC(═O)R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f),—C(═O)NR^(a)R^(h), —NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(h),—NR^(f)C(═O)NR^(a)R^(f), —NR^(f)CO₂R^(e), —C₁₋₈alylOR^(f),—C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f),—NR^(a)S(═O)₂R^(e), —OS(═O)₂R^(e), —OC(═O)NR^(a)R^(f), —OR^(h),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —NR^(a)R^(h),—NR^(f)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆NR^(a)R^(f),—NR^(h)C₂₋₆alkylOR^(f), —NR^(f)C₂₋₆alkylOR^(h), —CO₂R^(h), —OC(═O)R^(h),—C(═O)R^(h), —C(═O)NR^(a)R^(h), —NR^(f)C(═O)R^(h), —NR^(h)C(═O)R^(f),—NR^(h)C(═O)NR^(a)R^(f), —NR^(f)C(═O)NR^(a)R^(h), —NR^(h)CO₂R^(e),—NR^(f)CO₂R^(h), —C₁₋₈alkylOR^(h), —C₁₋₆alkylNR^(a)R^(h),—S(═O)_(n)R^(h), —S(═O)₂NR^(a)R^(h), —NR^(a)S(═O)₂R^(h),—NR^(h)S(═O)₂R^(e), —OS(═O)₂R^(h) and —OC(═O)NR^(a)R^(h);

R¹⁰ is independently, at each instance, selected from H, C₁₋₅alkyl,C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))R^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a) ^(f), —N(R^(a))C(═NR^(a))NR^(a)R,—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹⁰ is a saturated or unsaturated 5-, 6- or7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclicring containing 1, 2 or 3 atoms selected from N, O and S, wherein thereare no more than 2 N atoms, wherein the ring is substituted by 0, 1 or 2oxo or thioxo groups, wherein the ring is substituted by 0, 1, 2 or 3groups selected from R^(e), halo, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e)—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)F^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹⁰ is C₁₋₄alkyl substituted by 0, 1, 2 or 3groups selected from C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a) ₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a) R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆akylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h);

R¹¹ is independently, at each instance, selected from H, C₁₋₈alkyl,—C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f),—OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹¹ is a saturated or unsaturated 5-, 6- or7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclicring containing 1, 2 or 3 atoms selected from N, O and S, wherein thering is substituted by 0, 1 or 2 oxo or thioxo groups, wherein the ringis substituted by 0, 1, 2 or 3 groups selected from R^(e), halo, cyano,nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h)-OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a) R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹¹ is C₁₋₄alkyl substituted by 0, 1, 2 or 3groups selected from C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(h),—N(R^(h))S(═O)₂NR^(f), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹⁰ and R¹¹ together are a saturated orunsaturated 3-, 4- or 5-atom bridge containing 1, 2 or 3 atoms selectedfrom O, N and S with the remaining atoms being carbon, so long as thecombination of O and S atoms is not greater than 2, wherein the bridgeis substituted by 0, 1 or 2 substituents selected from oxo, thioxo,R^(c), R^(e), halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(h), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h)or R¹⁰ and R¹¹ together are a saturated orpartially unsaturated 3-, 4- or 5-carbon bridge, wherein the bridge issubstituted by 0, 1 or 2 substituents selected from oxo, thioxo, R^(c),R^(e), halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(l), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylO^(f) and—NR^(a)C₂₋₆alylOR^(h); and when R¹⁰ and R¹¹ together form a bridge, R¹²may additionally be halo or —CF₃, R¹³ may additionally be halo or—OR^(a) or cyano or nitro, and R¹⁴ may additionally be halo;

R¹² is independently, at each instance, selected from H, C₁₋₈alkyl,cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f) —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h),—OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)(NR^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a) R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹² is a saturated or unsaturated 5-, 6- or7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclicring containing 1, 2 or 3 atoms selected from N, O and S, wherein thering is substituted by 0, 1 or 2 oxo or thioxo groups, wherein the ringis substituted by 0, 1, 2 or 3 groups selected from R^(e), halo, cyano,nitro, —C(═O)R^(e), —C(═O)OR^(e), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹² is C₁₋₄alkyl substituted by 0, 1, 2 or 3groups selected from C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)R^(e) —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkYNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h) —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h) —NR^(h)C₂₋₆alkylOR^(f),—NR^(a)C₂₋₆alkylOR^(h), and additionally substituted by 0, 1 or 2 halogroups; or R¹¹ and R¹² together are a saturated or unsaturated 3-, 4- or5-atom bridge containing 1, 2 or 3 atoms selected from O, N and S withthe remaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2, wherein the bridge is substituted by 0, 1or 2 substituents selected from oxo, thioxo, R^(c), R^(e), halo, cyano,nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f) —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); wherein when R³ is NH₂, then —R¹¹—R¹²— is not—C═C—C═N— or any substituted version thereof; or R¹¹ and R¹² togetherare a saturated or partially unsaturated 3-, 4- or 5-carbon bridge,wherein the bridge is substituted by 0, 1 or 2 substituents selectedfrom oxo, thioxo, R^(c), R^(e), halo, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); and when R¹¹ and R¹² together form a bridge, R¹⁰may additionally be halo, R¹³ may additionally be halo or —OR^(a) orcyano or nitro, and R¹⁴ may additionally be halo;

R¹³ is independently, at each instance, selected from H, C₁₋₈alkyl,—C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f),—OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂N^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)₂R^(h),—C(O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹³ is a saturated or unsaturated 5-, 6- or7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclicring containing 1, 2 or 3 atoms selected from N, O and S, wherein thering is substituted by 0, 1 or 2 oxo or thioxo groups, wherein the ringis substituted by 0, 1, 2 or 3 groups selected from R^(e), halo, cyano,nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(e))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h) —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹³ is C₁₋₄alkyl substituted by 0, 1, 2 or 3groups selected from C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f)—N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e)—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h) —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f)—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h);

R¹⁴ is independently, at each instance, selected from H, C₁₋₅alkyl,C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkyNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f)—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹⁴ is a saturated or unsaturated 5-, 6- or7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclicring containing 1, 2 or 3 atoms selected from N, O and S, wherein thereare no more than 2 N atoms, wherein the ring is substituted by 0, 1 or 2oxo or thioxo groups, wherein the ring is substituted by 0, 1, 2 or 3groups selected from R^(e), halo, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f).—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹⁴ is C₁₋₄alkyl substituted by 0, 1, 2 or 3groups selected from C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(e),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f).—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a) R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and —NR^(a)C₂₋₆alkylOR^(h); wherein at least one of R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ isother than H;

R^(a) is independently, at each instance, H, phenyl, benzyl orC₁₋₆alkyl, the phenyl, benzyl and C₁₋₆alkyl being substituted by 0, 1, 2or 3 substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl,—OC₁₋₄alkyl, —NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C₁₋₄alkyl;

R^(b) is a heterocycle selected from the group of thiophene, pyrrole,1,3-oxazole, 1,3-thiazol-4-yl, 1,3,4-oxadiazole, 1,3,4-thiadiazole,1,2,3-oxadiazole, 1,2,3-thiadiazole, 1H-1,2,3-triazole, isothiazole,1,2,4-oxadiazole, 1,2,4-thiadiazole, 1,2,3,4-oxatriazole,1,2,3,4-thiatriazole, 1H-1,2,3,4-tetraazole, 1,2,3,5-oxatriazole,1,2,3,5-thiatriazole, furan, imidazol-2-yl, benzimidazole,1,2,4-triazole, isoxazole, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl,thiolane, pyrrolidine, tetrahydrofuran, 4,5-dihydrothiophene,2-pyrroline, 4,5-dihydrofuran, pyridazine, pyrimidine, pyrazine,1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, pyridine,2H-3,4,5,6-tetrahydropyran, thiane, 1,2-diazaperhydroine,1,3-diazaperhydroine, piperazine, 1,3-oxazaperhydroine, morpholine,1,3-thiazaperhydroine, 1,4-thiazaperhydroine, piperidine,2H-3,4-dihydropyran, 2,3-dihydro-4H-thiin, 1,4,5,6-tetrahydropyridine,2H-5,6-dihydropyran, 2,3-dihydro-6H-thiin, 1,2,5,6-tetrahydropyridine,3,4,5,6-tetrahydropyridine, 4H-pyran, 4H-thiin, 1,4-dihydropyridine,1,4-dithiane, 1,4-dioxane, 1,4-oxathiane, 1,2-oxazolidine,1,2-thiazolidine, pyrazolidine, 1,3-oxazolidine, 1,3-thiazolidine,imidazolidine, 1,2,4-oxadiazolidine, 1,3,4-oxadiazolidine,1,2,4-thiadiazolidine, 1,3,4-thiadiazolidine, 1,2,4-triazolidine,2-imidazolin-1-yl, 2-imidazolin-2-yl, 3-imidazoline, 2-pyrazoline,4-imidazoline, 2,3-dihydroisothiazole, 4,5-dihydroisoxazole,4,5-dihydroisothiazole, 2,5-dihydroisoxazole, 2,5-dihydroisothiazole,2,3-dihydroisoxazole, 4,5-dihydrooxazole, 2,3-dihydrooxazole,2,5-dihydrooxazole, 4,5-dihydrothiazole, 2,3-dihydrothiazole,2,5-dihydrothiazole, 1,3,4-oxathiazolidine, 1,4,2-oxathiazolidine,2,3-dihydro-1H-[1,2,3]triazole, 2,5-dihydro-1H-[1,2,3]triazole,4,5-dihydro-1H-[1,2,3]triazol-1-yl, 4,5-dihydro-1H-[1,2,3]triazol-3-yl,4,5-dihydro-1H-[1,2,3]triazol-5-yl, 2,3-dihydro-1H-[1,2,4]triazole,4,5-dihydro-1H-[1,2,4]triazole, 2,3-dihydro-[1,2,4]oxadiazole,2,5-dihydro-[1,2,4]oxadiazole, 4,5-dihydro-[1,2,4]thiadiazole,2,3-dihydro-[1,2,4] thiadiazole, 2,5-dihydro-[1,2,4] thiadiazole,4,5-dihydro-[1,2,4] thiadiazole, 2,5-dihydro-[1,2,4]oxadiazole,2,3-dihydro-[1,2,4]oxadiazole, 4,5-dihydro-[1,2,4]oxadiazole,2,5-dihydro-[1,2,4]thiadiazole, 2,3-dihydro-[1,2,4] thiadiazole,4,5-dihydro-[1,2,4] thiadiazole, 2,3-dihydro-[1,3,4]oxadiazole,2,3-dihydro-[1,3,4]thiadiazole, [1,4,2]oxathiazole, [1,3,4]oxathiazole,1,3,5-triazaperhydroine, 1,2,4-triazaperhydroine,1,4,2-dithiazaperhydroine, 1,4,2-dioxazaperhydroine,1,3,5-oxadiazaperhydroine, 1,2,5-oxadiazaperhydroine,1,3,4-thiadiazaperhydroine, 1,3,5-thiadiazaperhydroine,1,2,5-thiadiazaperhydroine, 1,3,4-oxadiazaperhydroine,1,4,3-oxathiazaperhydroine, 1,4,2-oxathiazaperhydroine,1,4,5,6-tetrahydropyridazine, 1,2,3,4-tetrahydropyridazine,1,2,3,6-tetrahydropyridazine, 1,2,5,6-tetrahydropyrimidine,1,2,3,4-tetrahydropyrirnidine, 1,4,5,6-tetrahydropyrimidine,1,2,3,6-tetrahydropyrazine, 1,2,3,4-tetrahydropyrazine,5,6-dihydro-4H-[1,2]oxazine, 5,6-dihydro-2H-[1,2]oxazine,3,6-dihydro-2H-[1,2]oxazine, 3,4-dihydro-2H-[1,2]oxazine,5,6-dihydro-4H-[1,2]thiazine, 5,6-dihydro-2H-[1,2] thiazine,3,6-dihydro-2H-[1,2] thiazine, 3,4-dihydro-2H-[1,2] thiazine,5,6-dihydro-2H-[1,3]oxazine, 5,6-dihydro-4H-[1,3]oxazine,3,6-dihydro-2H-[1,3]oxazine, 3,4-dihydro-2H-[1,3]oxazine,3,6-dihydro-2H-[1,4]oxazine, 3,4-dihydro-2H-[1,4]oxazine,5,6-dihydro-2H-[1,3]thiazine, 5,6-dihydro-4H-[1,3]thiazine,3,6-dihydro-2H-[1,3]thiazine, 3,4-dihydro-2H-[1,3]thiazine,3,6-dihydro-2H-[1,4]thiazine, 3,4-dihydro-2H-[1,4]thiazine,1,2,3,6-tetrahydro-[1,2,4]triazine, 1,2,3,4-tetrahydro-[1,2,4]triazine,1,2,3,4-tetrahydro-[1,3,5]triazine, 2,3,4,5-tetrahydro-[1,2,4]triazine,1,4,5,6-tetrahydro-[1,2,4]triazine, 5,6-dihydro-[1,4,2]dioxazine,5,6-dihydro-[1,4,2]dithiazine, 2,3-dihydro-[1,4,2]dioxazine,3,4-dihydro-2H-[1,3,4]oxadiazine, 3,6-dihydro-2H-[1,3,4]oxadiazine,3,4-dihydro-2H-[1,3,5]oxadiazine, 3,6-dihydro-2H-[1,3,5]oxadiazine,5,6-dihydro-2H-[1,2,5]oxadiazine, 5,6-dihydro-4H-[1,2,5]oxadiazine,3,4-dihydro-2H-[1,3,4]thiadiazine, 3,6-dihydro-2H-[1,3,4]thiadiazine,3,4-dihydro-2H-[1,3,5]thiadiazine, 3,6-dihydro-2H-[1,3,5]thiadiazine,5,6-dihydro-2H-[1,2,5]thiadiazine, 5,6-dihydro-4H-[1,2,5]thiadiazine,5,6-dihydro-2H-[1,2,3]oxadiazine, 3,6-dihydro-2H-[1,2,5]oxadiazine,5,6-dihydro-4H-[1,3,4]oxadiazine, 3,4-dihydro-2H-[1,2,5]oxadiazine,5,6-dihydro-2H-[1,2,3]thiadiazine, 3,6-dihydro-2H-[1,2,5]thiadiazine,5,6-dihydro-4H-[1,3,4]thiadiazine, 3,4-dihydro-2H-[1,2,5]thiadiazine,5,6-dihydro-[1,4,3]oxathiazine, 5,6-dihydro-[1,4,2]oxathiazine,2,3-dihydro-[1,4,3]oxathiazine, 2,3-dihydro-[1,4,2]oxathiazine,3,4-dihydropyridine, 1,2-dihydropyridine, 5,6-dihydropyridine, 2H-pyran,2H-thiin, 3,6-dihydropyridine, 2,3-dihydropyridazine,2,5-dihydropyridazine, 4,5-dihydropyridazine, 1,2-dihydropyridazine,1,4-dihydropyrimidin-1-yl, 1,4-dihydropyrimidin-4-yl,1,4-dihydropyrimidin-5-yl, 1,4-dihydropyrimidin-6-yl,2,3-dihydropyrimidine, 2,5-dihydropyrimidine, 5,6-dihydropyrimidine,3,6-dihydropyrimidine, 5,6-dihydropyrazine, 3,6-dihydropyrazine,4,5-dihydropyrazine, 1,4-dihydropyrazine, 1,4-dithiin, 1,4-dioxin,2H-1,2-oxazine, 6H-1,2-oxazine, 4H-1,2-oxazine, 2H-1,3-oxazine,4H-1,3-oxazine, 6H-1,3-oxazine, 2H-1,4-oxazine, 4H-1,4-oxazine,2H-1,3-thiazine, 2H-1,4-thiazine, 4H-1,2-thiazine, 6H-1,3-thiazine,4H-1,4-thiazine, 2H-1,2-thiazine, 6H-1,2-thiazine, 1,4-oxathiin,2H,5H-1,2,3-triazine, 1H,4H-1,2,3-triazine, 4,5-dihydro-1,2,3-triazine,1H,6H-1,2,3-triazine, 1,2-dihydro-1,2,3-triazine,2,3-dihydro-1,2,4-triazine, 3H,6H-1,2,4-triazine, 1H,6H-1,2,4-triazine,3,4-dihydro-1,2,4-triazine, 1H,4H-1,2,4-triazine,5,6-dihydro-1,2,4-triazine, 4,5-dihydro-1,2,4-triazine,2H,5H-1,2,4-triazine, 1,2-dihydro-1,2,4-triazine, 1H,4H-1,3,5-triazine,1,2-dihydro-1,3,5-triazine, 1,4,2-dithiazine, 1,4,2-dioxazine,2H-1,3,4-oxadiazine, 1,2-dihydro-1,3,5-oxadiazine, 6H-1,2,5-oxadiazine,4H-1,3,4-oxadiazine, 4H-1,3,5-oxadiazine, 4H-1,2,5-oxadiazine,2H-1,3,5-thiadiazine, 6H-1,2,5-thiadiazine, 4H-1,3,4-thiadiazine,4H-1,3,5-thiadiazine, 4H-1,2,5-thiadiazine, 2H-1,3,4-thiadiazine,6H-1,3,4-thiadiazine, 6H-1,3,4-oxadiazine, and 1,4,2-oxathiazine,wherein the heterocycle is optionally vicinally fused with a saturatedor unsaturated 5-, 6- or 7-membered ring containing 0, 1 or 2 atomsindependently selected from N, O and S;

R^(c) is independently, in each instance, phenyl substituted by 0, 1 or2 groups selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OR^(a) and—NR^(a)R^(a); or R^(c) is a saturated or unsaturated 5- or 6-memberedring heterocycle containing 1, 2 or 3 heteroatoms independently selectedfrom N, O and S, wherein no more than 2 of the ring members are O or S,wherein the heterocycle is optionally fused with a phenyl ring, and thecarbon atoms of the heterocycle are substituted by 0, 1 or 2 oxo orthioxo groups, wherein the heterocycle or fused phenyl ring issubstituted by 0, 1, 2 or 3 substituents selected from halo, C₁₋₄alkyl,C₁₋₃haloalkyl, —OR^(a) and —NR^(a)R^(a);

R^(d) is independently in each instance hydrogen or —CH₃;

R^(e) is, independently, in each instance, C₁₋₉alkyl or C₄alkyl(phenyl)wherein either is substituted by 0, 1, 2, 3 or 4 substituents selectedfrom halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(e),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(e),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(a)—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(e), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(e),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆akylOR^(a); and wherein theC₁₋₆alkyl is additionally substituted by 0 or 1 groups independentlyselected from R^(h);

R^(f) is, independently, in each instance, R^(e) or H;

R^(g) is, independently, in each instance, a saturated or unsaturated 5-or 6-membered monocyclic ring containing 1, 2 or 3 atoms selected fromN, O and S, so long as the combination of O and S atoms is not greaterthan 2, wherein the ring is substituted by 0 or 1 oxo or thioxo groups;and

R^(h) is, independently, in each instance, phenyl or a saturated orunsaturated 5- or 6-membered monocyclic ring containing 1, 2 or 3 atomsselected from N, O and S, so long as the combination of O and S atoms isnot greater than 2, wherein the ring is substituted by 0 or 1 oxo orthioxo groups, wherein the phenyl or monocycle are substituted by 0, 1,2 or 3 substituents selected from halo, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(e), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(f), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(e), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f)—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(e),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f) and —NR^(a)C₂₋₆alkylOR^(f).

In one embodiment, in conjunction with any one of the above and belowembodiments, X is N or C(R²); Y is N or C(R³), wherein at least one of Xand Y is not N.

In another embodiment, in conjunction with any one of the above andbelow embodiments, X is C(R²); Y is C(R³); and R³ is halo, —NH₂,—NHC₁₋₃alkyl, —N(C₁₋₃alkyl)C₁₋₃alkyl, or C₁₋₃alkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, X is C(R²); Y is C(R³); and R³ is H;

In another embodiment, in conjunction with any one of the above andbelow embodiments, X is N; and Y is C(R³).

In another embodiment, in conjunction with any one of the above andbelow embodiments, X is C(R²); and Y is N.

Embodiment A: In another embodiment, in conjunction with any one of theabove and below embodiments, R¹ is

or R¹ is R^(b) substituted by 1, 2 or 3 substituents independentlyselected from R^(f), R^(g), halo, nitro, cyano, —OR^(e), —OR^(g),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and R^(b) is additionally substituted by 0, 1 or 2groups independently selected from R^(c); or R¹ is phenyl that isvicinally fused with a saturated or unsaturated 3-, 4- or 5-atom bridgecontaining 0, 1, 2 or 3 atoms selected from O, N and S with theremaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2, wherein the heterocycle and bridge aresubstituted by 0, 1, 2 or 3 substituents independently selected from R⁵.

Embodiment B: In another embodiment, in conjunction with any one of theabove and below embodiments, R¹ is

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is phenyl that is vicinally fused with a saturatedor unsaturated 3-, 4- or 5-atom bridge containing 0, 1, 2 or 3 atomsselected from O, N and S with the remaining atoms being carbon, so longas the combination of O and S atoms is not greater than 2, wherein theheterocycle and bridge are substituted by 0, 1, 2 or 3 substituentsindependently selected from R⁵.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is phenyl that is vicinally fused with a saturatedor unsaturated 3-, 4- or 5-atom bridge containing 1, 2 or 3 atomsselected from O, N and S with the remaining atoms being carbon, so longas the combination of O and S atoms is not greater than 2, wherein theheterocycle and bridge are substituted by 0, 1, 2 or 3 substituentsindependently selected from R⁵.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is phenyl that is vicinally fused with a saturatedor unsaturated 3-, 4- or 5-atom bridge containing 1, 2 or 3 atomsselected from O, N and S with the remaining atoms being carbon, so longas the combination of O and S atoms is not greater than 2, wherein theheterocycle and bridge are substituted by 0, 1, 2 or 3 substituentsindependently selected from R⁵.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is naphthyl substituted by 0, 1, 2 or 3substituents independently selected from R⁵.

Embodiment C: In another embodiment, in conjunction with any one of theabove and below embodiments, R¹ is R^(b) substituted by 1, 2 or 3substituents independently selected from R^(f), R^(g), halo, nitro,cyano, —OR^(e), —OR^(g), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—NR^(a)R^(f), —NR^(a)R^(g), —NR^(f)C₂₋₆alkylNR^(a)R^(f),—NR^(f)C₂₋₆alkylOR^(f), naphthyl, —CO₂R^(e), —C(═O)R^(e),—C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g), —NR^(f)C(═O)R^(e),—NR^(f)(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f), —NR^(f)CO₂R^(e),—C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e),—S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and —OC(═O)NR^(a)R^(f), and R^(b)is additionally substituted by 0, 1 or 2 groups independently selectedfrom R^(c).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R² is, independently, in each instance, R¹⁴, halo,C₁₋₈alkyl substituted by 0, 1 or 2 substituents selected from R¹⁴ andhalo, —(CH₂)_(n)phenyl substituted by 0, 1, 2 or 3 substituentsindependently selected from R¹⁴ and halo, or a saturated or unsaturated5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatomsindependently selected from N, O and S, wherein no more than 2 of thering members are O or S, wherein the heterocycle is optionally fusedwith a phenyl ring, and the heterocycle or fused phenyl ring issubstituted by 0, 1, 2 or 3 substituents independently selected from R¹⁴and halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R² is, independently, in each instance, R¹⁴ or halo,C₁₋₈alkyl substituted by 0, 1 or 2 substituents selected from R¹⁴ andhalo, —(CH₂)phenyl substituted by 0, 1, 2 or 3 substituentsindependently selected from R¹⁴ and halo, or a saturated or unsaturated5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatomsindependently selected from N, O and S, wherein no more than 2 of thering members are O or S, wherein the heterocycle is optionally fusedwith a phenyl ring, and the heterocycle or fused phenyl ring issubstituted by 0, 1, 2 or 3 substituents independently selected from R¹⁴and halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R² is C₁₋₈alkyl substituted by 0, 1 or 2 substituentsselected from R¹⁴ and halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R^(2 is —(CH) ₂)₁₋₂phenyl substituted by 0, 1, 2 or 3substituents independently selected from R¹⁴ and halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R² is a saturated or unsaturated 5- or 6-memberedring heterocycle containing 1, 2 or 3 heteroatoms independently selectedfrom N, O and S, wherein no more than 2 of the ring members are O or S,wherein the heterocycle is optionally fused with a phenyl ring, and theheterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3substituents independently selected from R¹⁴ and halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R² is H.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R² is —OR⁴ or —N(R^(a))R⁴.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R² is —OR⁴.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R² is —N(R^(a))R⁴.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R³ is, independently, in each instance, H, halo,—NH₂, —NHC₁₋₃alkyl, —N(C₁₋₃alkyl)C₁₋₃alkyl, or C₁₋₃alkyl; wherein, whenX is C(R²) and Y is C(R³) then at least one of R² and R³ is other thanH.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R³ is halo, —NH₂, —NHC₁₋₃alkyl,—N(C₁₋₃alkyl)C₁₋₃alkyl, or C₁₋₃alkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R³ is H.

Embodiment D: In another embodiment, in conjunction with any one of theabove and below embodiments, R⁴ is independently at each instance

R⁴ is independently at each instance a saturated or unsaturated 5- or6-membered ring heterocycle containing 1, 2 or 3 atoms selected from O,N and S that is optionally vicinally fused with a saturated orunsaturated 3-, 4- or 5-atom bridge containing 0, 1, 2 or 3 atomsselected from O, N and S with the remaining atoms being carbon, so longas the combination of O and S atoms is not greater than 2, wherein theheterocycle and bridge are substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(e), C₁₋₅haloalkyl, halo, cyano, oxo,thioxo, —OR^(f), —S(═O)_(n)R^(e), —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —OC₁₋₆alkylC(═O)OR^(e),—NR^(a)R^(f), —NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(e), —C(═O)OR^(f), —OC(═O)R^(e),—C(═O)NR^(a)R^(f) and —NR^(a)C(═O)R^(e); or R⁴ is independently at eachinstance naphthyl substituted by 1, 2 or 3 substituents independentlyselected from C₁₋₄haloalkyl, halo, nitro, cyano, —S(═O)_(n)R^(e),—OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—OC₁₋₆alkylC(═O)OR^(e), —NR^(a)C₁₋₄haloalkyl,—NR^(a)C₂₋₆alkylN^(a)R^(f), —NR^(a)C₂₋₆alylkOR^(f), —C(═O)R^(e),—C(═O)OR^(f), —OC(═O)R^(e) and —C(═O)NR^(a)R^(f); but in no instance isR⁴-phenyl-(C₁₋₈alkyl), -phenyl-O-(C₁₋₆alkyl), -phenyl-NR^(a)R^(a) or-phenyl-N(R^(a))C(═O)(C₁₋₈alkyl).

Embodiment E: In another embodiment, in conjunction with any one of theabove and below embodiments, R⁴ is independently at each instance

but in no instance is R⁴-phenyl-O—(C₁₋₆alkyl), -phenyl-NR^(a)R^(a) or-phenyl-N(R^(a))C(═O)(C₁₋₆alkyl).

Embodiment F: In another embodiment, in conjunction with any one of theabove and below embodiments, R⁴ is independently at each instance asaturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fusedwith a saturated or unsaturated 3-, 4- or 5-atom bridge containing 0, 1,2 or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, wherein the heterocycle and bridge are substituted by 0, 1, 2 or 3substituents independently selected from R^(e), C₁₋₄haloalkyl, halo,cyano, oxo, thioxo, —OR^(f), —S(═O),R^(e), —OC₁₋₄aloalkyl,—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —OC₁₋₆alkylC(═O)OR^(e),—NR^(a)R^(f), —NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(e), —C(═O)OR^(f), —OC(═O)R^(e),—C(═O)NR^(a)R^(f) and —NR^(a)C(═O)R^(e).

Embodiment G: In another embodiment, in conjunction with any one of theabove and below embodiments, R⁴ is independently at each instance asaturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S that is vicinally fused with asaturated or unsaturated 3-, 4- or 5-atom bridge containing 0, 1, 2 or 3atoms selected from O, N and S with the remaining atoms being carbon, solong as the combination of O and S atoms is not greater than 2, whereinthe heterocycle and bridge are substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(e), C₁₋₄haloalkyl, halo, cyano, oxo,thioxo, —OR^(f), —S(═O)_(n)R^(e), —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —OC₁₋₆alkylC(═O)OR^(e),—NR^(a)R^(f), —NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(e), —C(═O)OR^(f), —OC(═O)R^(e),—C(═O)NR^(a)R^(f) and —NR^(a)C(═O)R^(e).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is independently at each instance naphthylsubstituted by 1, 2 or 3 substituents independently selected fromC₁₋₄haloalkyl, halo, nitro, cyano, —S(═O)_(n)R^(e), —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —OC₁₋₆alkylC(═O)OR^(e),—NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(e), —C(═O)OR^(f), —OC(═O)R^(e) and—C(═O)NR^(a)R^(f).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁵ is independently, at each instance, R^(f), R^(h),halo, nitro, cyano, —OR^(f), —OR^(h), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(f),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —OC(═O)R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f),—C(═O)NR^(a)R^(h), —NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(h),—NR^(f)C(═O)NR^(a)R^(f), —NR^(f)CO₂R^(e), —C₁l₈alkylOR^(f),—C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f),—NR^(a)S(═O)₂R^(e), —OS(═O)₂R^(e), —OC(═O)NR^(a)R^(f), —OR^(h),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —NR^(a)R^(h),—NR^(f)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(h)C₂₋₆alkylOR^(f), —NR^(f)C₂₋₆alkylOR^(h), —CO₂R^(h), —OC(═O)R^(h),—C(═O)R^(h), —C(═O)NR^(a)R^(h), —NR^(f)C(═O)R^(h), —NR^(h)C(═O)R^(f),—NR^(h)C(═O)NR^(a)R^(f), —NR^(f)C(═O)NR^(a)R^(h), —NR^(h)CO₂R^(e),—NR^(f)CO₂R^(h), —C₁₋₈alkylOR^(h), —C₁₋₆alkylNR^(a)R^(h),—S(═O)_(n)R^(h), —S(═O)₂NR^(a)R^(h), —NR^(a)S(═O)₂R^(h),—NR^(h)S(═O)₂R^(e), —OS(═O)₂R^(h) or —OC(═O)NR^(a)R^(h).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁵ is H.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁵ is R^(f) or R^(h).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁵ is independently, at each instance, R^(f), halo,nitro, cyano, —OR^(f), —OR^(h), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(h),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), —CO₂R^(e),—OC(═O)R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(h),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(h), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₂₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e), —OS(═O)₂R^(e),—OC(═O)NR^(a)R^(f), —OR^(h), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—NR^(a)R^(h), —NR^(f)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(h),—NR^(h)C₂₋₆alkylOR^(f), —NR^(f)C₂₋₆alkylOR^(h), —CO²R^(h), —OC(═O)R^(h),—C(═O)R^(h), —C(═O)NR^(a)R^(h), —NR^(f)C(═O)R^(h), —NR^(h) C(═O)R^(f),—NR^(h)C(═O)NR^(a)R^(f), —NR^(f)C(═O)NR^(a)R^(h), —NR^(h)CO₂R^(e),—NR^(f)CO₂R^(h), —C₁₋₈alkylOR^(h), —C₁₋₆alkylNR^(a)R^(h),—S(═O)_(n)R^(h), —S(═O)₂NR^(a)R^(h), —NR^(a)S(═O)₂R^(h),—NR^(h)S(═O)₂R^(e), —OS(═O)₂R^(h), or —OC(═O)NR^(a)R^(h).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁵ is independently, at each instance, H or a phenylring substituted with 0, 1, 2, or 3 substituents independently selectedfrom R¹⁴ and halo; or R⁵ is a saturated or unsaturated 5- or 6-memberedring heterocycle containing 1, 2 or 3 atoms selected from O, N and S,substituted with 0, 1, 2, or 3 substituents independently selected fromR¹⁴ and halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁵ is independently, at each instance, H or R⁵ is asaturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S, substituted with 0, 1, 2, or 3substituents independently selected from R¹⁴ and halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁶ is independently, at each instance, H, C₁₋₅alkyl,C₁₋₄haloalkyl, halo, nitro —OR^(e), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —NR^(a)R^(a), —NR^(a)C₁₋₄haloalkyl,—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a),—C₁₋₆alkylNR^(a)R^(a), —S(C₁₋₆alkyl), a phenyl ring substituted with 1,2, or 3 substituents independently selected from R¹⁴ and halo; or R⁶ isa saturated or unsaturated 5- or 6-membered ring heterocycle containing1, 2 or 3 atoms selected from O, N and S substituted with 0, 1, 2, or 3substituents independently selected from R¹⁴ and halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁶ is independently, at each instance, C₁₋₅alkyl,C₁₋₄haloalkyl, halo, nitro —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a)—OC₂₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a) or—NR^(a)C₂₋₆alkylOR^(a), C₁₋₈alkylOR^(a), —C₁₋₆ alkylNR^(a)R^(a),—S(C¹⁻⁶alkyl), a phenyl ring substituted with 1, 2, or 3 substituentsindependently selected from R¹⁴ and halo; or R⁶ is a saturated orunsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atomsselected from O, N and S substituted with 0, 1, 2, or 3 substituentsindependently selected from R¹⁴ and halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁶ is independently, at each instance, C₁₋₅alkyl,C₁₋₄haloalkyl, halo, —OC₁₋₆alkyl, —OC₁₋₆haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)C₁₋₆haloalkyl, —NR^(a)C₂₋₆alylNR^(a)R^(a) or—NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a) or—S(C₁₋₆alkyl).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁶ is a phenyl ring substituted with 1, 2, or 3substituents independently selected from R¹⁴ and halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁶ is a saturated or unsaturated 5- or 6-memberedring heterocycle containing 1, 2 or 3 atoms selected from O, N and Ssubstituted with 0, 1, 2, or 3 substituents independently selected fromR¹⁴ and halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁶ is H.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁷ is independently, at each instance, H, C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a) or—S(C₁₋₆alkyl); or R⁷ is a saturated or unsaturated 4- or 5-membered ringheterocycle containing a single nitrogen atom, wherein the ring issubstituted with 0, 1 or 2 substituents independently selected fromhalo, C₁₋₂haloalkyl and C₁₋₃alkyl.

Embodiment H: In another embodiment, in conjunction with any one of theabove and below embodiments, R⁷ is independently, at each instance,C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, —OR^(e), —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a) or—S(C₁₋₆alkyl); or R⁷ is a saturated or unsaturated 4- or 5-membered ringheterocycle containing a single nitrogen atom, wherein the ring issubstituted with 0, 1 or 2 substituents independently selected fromhalo, C₁₋₂haloalkyl and C₁₋₃alkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁷ is H.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁷ is a saturated or unsaturated 4- or 5-memberedring heterocycle containing a single nitrogen atom, wherein the ring issubstituted with 0, 1 or 2 substituents independently selected fromhalo, C₁₋₂haloalkyl and C₁₋₃alkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁷ is independently, at each instance,acyclicC₁₋₈alkyl, C₁₋₄haloalkyl, halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a) or—S(C₁₋₆alkyl).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁷ is independently, at each instance,acyclicC₁₋₈alkyl, C₁₋₄haloalkyl, Br, or Cl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁷ is independently, at each instance,acyclicC₁₋₈alkyl or C₁₋₄haloalkyl.

Embodiment I: In another embodiment, in conjunction with any one of theabove and below embodiments, R⁷ is independently, at each instance,C₃₋₅alkyl or C₁₋₂haloalkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁷ is C₃₋₅alkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁷ is —C(CH₃)₃.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁷ is —CF₃.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁸ is independently, at each instance, H, C₁₋₅alkyl,C₁₋₄haloalkyl, halo, nitro, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a),—S(C₁₋₆alkyl), a phenyl ring substituted with 1, 2, or 3 substituentsindependently selected from R¹⁴ and halo, or R⁸ is a saturated orunsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atomsselected from O, N and S substituted with 0, 1, 2, or 3 substituentsindependently selected from R¹⁴ and halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁸ is H.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁸ is independently, at each instance, C₁₋₅alkyl,C₁₋₄haloalkyl, halo, nitro, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a), —NR^(a)C,haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a),—C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a), —S(C₁₋₆alkyl), a phenyl ringsubstituted with 1, 2, or 3 substituents independently selected from R¹⁴and halo, or R⁸ is a saturated or unsaturated 5- or 6-membered ringheterocycle containing 1, 2 or 3 atoms selected from O, N and Ssubstituted with 0, 1, 2, or 3 substituents independently selected fromR¹⁴ and halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁸ is independently, at each instance, C₁₋₅alkyl,C₁₋₄haloalkyl, halo, nitro, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a), —NR^(a)C1-4haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a),—C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a) or —S(C₁₋₆alkyl).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁸ is a phenyl ring substituted with 1, 2, or 3substituents independently selected from R¹⁴ and halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁸ is a saturated or unsaturated 5- or 6-memberedring heterocycle containing 1, 2 or 3 atoms selected from O, N and Ssubstituted with 0, 1, 2, or 3 substituents independently selected fromR¹⁴ and halo.

Embodiment J: In another embodiment, in conjunction with any one of theabove and below embodiments, R⁹ is independently, at each instance,R^(f), R^(g), halo, nitro, cyano, —OR^(f), —OR^(h),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(h),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —OC(═O)R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f),—C(═O)NR^(a)R^(f), —NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(h),—NR^(f)C(═O)NR^(a)R^(f), —NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f),—C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(h),—NR^(a)S(═O)₂R^(e), —OS(═O)₂R^(e), —OC(═O)NR^(a)R^(f), —OR^(h),—OC₂₋₆alkylNR^(a)R, —OC₂₋₆alkylOR^(f), —NR^(a)R^(h),—NR^(f)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(h)C₂₋₆alkylOR^(f), —NR^(f)C₂₋₆alkylOR^(h), —CO₂R^(h), —OC(═O)R^(h),—C(═O)R^(h), —C(═O)NR^(a)R^(h), —NR^(f)C(═O)R^(h), —NR^(h)C(═O)R^(f),—NR^(h)C(═O)NR^(a)R^(f), —NR^(f)C(═O)NR^(a)R^(h), —NR^(h)CO₂R^(e),—NR^(f)CO₂R^(h), —C₁₋₈alkylOR^(h), —C₁₋₆alkylNR^(a)R^(h),—S(═O)_(n)R^(h), —S(═O)₂NR^(a)R^(h), —NR^(a)S(═O)₂R^(h),—NR^(h)S(═O)₂R^(e), —OS(═O)₂R^(h), —OC(═O)NR^(a)R^(h), a phenyl ringsubstituted with 0, 1, 2, or 3 substituents independently selected fromR¹⁴ and halo; or R⁹ is a saturated or unsaturated 5- or 6-membered ringheterocycle containing 1, 2 or 3 atoms selected from O, N and Ssubstituted with 0, 1, 2, or 3 substituents independently selected fromR¹⁴ and halo; or R⁹ is a saturated or unsaturated 4- or 5-membered ringheterocycle containing a single nitrogen atom, wherein the ring issubstituted with 0, 1 or 2 substituents independently selected fromhalo, C₁₋₂haloalkyl and C₁₋₃alkyl.

Embodiment K: In another embodiment, in conjunction with any one of theabove and below embodiments, R⁹ is H.

Embodiment L: In another embodiment, in conjunction with any one of theabove and below embodiments, R⁹ is independently, at each instance,R^(e), R^(g), halo, nitro, cyano, —OR^(f), —OR^(h),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(h),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —OC(═O)R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f),—C(═O)NR^(a)R^(h), —NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(h),—NR^(f)C(═O)NR^(a)R^(f), —NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f),—C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f),—NR^(a)S(═O)₂R^(e), —OS(═O)₂R^(e), —OC(═O)NR^(a)R^(f), —OR^(h),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(f), —NR^(a)R^(h),—NR^(f)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(h)C₂₋₆alkylOR^(f), —NR^(f)C₂₋₆alkylOR^(h), —CO₂R^(h), —OC(═O)R^(h),—C(═O)R^(h), —C(═O)NR^(a)R^(h), —NR^(f)C(═O)R^(h), —NR^(h)C(═O)R^(f),—NR^(h)C(═O)NR^(a)R^(f), —NR^(f)C(═O)NR^(a)R^(h), —NR^(h)CO₂R^(e),—NR^(f)CO₂R^(h), —C₁₋₈alkylOR^(h), —C₁₋₆alkylNR^(a)R^(h),—S(═O)_(n)R^(h), —S(═O)₂NR^(a)R^(l), —NR^(a)S(═O)₂R^(h),—NR^(h)S(═O)₂R^(e), —OS(═O)₂R^(h), —OC(═O)NR^(a)R^(h), a phenyl ringsubstituted with 0, 1, 2, or 3 substituents independently selected fromR¹⁴ and halo; or R⁹ is a saturated or unsaturated 5- or 6-membered ringheterocycle containing 1, 2 or 3 atoms selected from O, N and Ssubstituted with 0, 1, 2, or 3 substituents independently selected fromR¹⁴ and halo; or R⁹ is a saturated or unsaturated 4- or 5-membered ringheterocycle containing a single nitrogen atom, wherein the ring issubstituted with 0, 1 or 2 substituents independently selected fromhalo, C₁₋₂haloalkyl and C₁₋₃alkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁹ is independently, at each instance, R^(e).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁹ is independently, at each instance, R^(g).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁹ is independently, at each instance, halo, nitro,cyano, —OR^(e), —OR^(g), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—NR^(a)R^(f), —NR^(a)R^(g), —NR^(f)C₂₋₆alkylNR^(a)R^(f),—NR^(f)C₂₋₆alkylOR^(f), —CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f),—C(═O)NR^(a)R^(g), —NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g),—NR^(f)C(═O)NR^(a)R^(f), —NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f),—C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e), —S(═)₂NR^(a)R^(f),—NR^(a)S(═O)₂R^(e) or —OC(═O)NR^(a)R^(f).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁹ is independently, at each instance, a phenyl ringsubstituted with 0, 1, 2, or 3 substituents independently selected fromR¹⁴ and halo; or R⁹ is a saturated or unsaturated 5- or 6-membered ringheterocycle containing 1, 2 or 3 atoms selected from O, N and Ssubstituted with 0, 1, 2, or 3 substituents independently selected fromR¹⁴ and halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁹ is a saturated or unsaturated 4- or 5-memberedring heterocycle containing a single nitrogen atom, wherein the ring issubstituted with 0, 1 or 2 substituents independently selected fromhalo, C₁₋₂haloalkyl and C₁₋₃alkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, at least one of R⁵, R⁶, R⁷, R⁸ and R⁹ is R^(e),R^(h), halo, nitro, cyano, —OR^(h), —NR^(a)R^(f), —NR^(a)R^(h),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —OC(═O)R^(e), —C(═O)NR^(a)R^(f),—C(═O)NR^(a)R^(f), —NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(h),—NR^(f)C(═O)NR^(a)R^(f), —NR^(f)CO₂R^(e), —C₂₋₆alkylOR^(f),—C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f),—NR^(a)S(═O)₂R^(e), —OS(═O)₂R^(e), —OC(═O)NR^(a)R^(f), —OR^(h),—OC₂₋₆alkylNR^(a)R^(h), —NR^(f)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂alkylNR^(a)R^(f), —NR^(h)C₂₋₆alkylOR^(f), —NR^(f)C₂₋₆alkylOR^(h),—CO₂R^(h), —OC(═O)R^(h), —C(═O)R^(h), —C(═O)NR^(a)R^(h),—NR^(f)C(═O)R^(h), —NR^(h)C(═O)R^(f), —NR^(h)C(═O)NR^(a)R^(f),—NR^(f)C(═O)NR^(a)R^(h), —NR^(h)CO₂R^(e), —NR^(f)CO₂R^(h),—C₁₋₈alkylOR^(h), —C₁₋₆alkylNR^(a)R^(h), —S(═O)_(n)R^(h),—S(═O)₂NR^(a)R^(h), —NR^(a)S(═O)₂R^(h), —NR^(h)S(═O)₂R^(e),—OS(═O)₂R^(h), —OC(═O)NR^(a)R^(h), or —OC₁₋₈alkyl substituted by 1, 2 or3 substituents independently selected from R^(f), R^(h), halo, nitro,cyano, —OR^(f), —OR^(h), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—NR^(a)R^(f), —NR^(a)R^(f), —NR^(f)C₂₋₆alkylNR^(a)R^(f),—NR^(f)C₂₋₆alkylOR^(f), naphthyl, —CO₂R^(e), —OC(═O)R^(e), —C(═O)R^(e),—C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(h), —NR^(f)C(═O)R^(e),—NR^(f)C(═O)R^(h), —NR^(f)C(═O)NR^(a)R^(f), —NR^(f)CO₂R^(e),—C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e),—S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e), —OS(═O)₂R^(e),—OC(═O)NR^(a)R^(f), —OR^(h), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—NR^(a)R^(h), —NR^(f)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(h)C₂₋₆alkylOR^(f), —NR^(f)C₂₋₆alkylOR^(h), —CO₂R^(h), —OC(═O)R^(h),—C(═O)R^(h), —C(═O)NR^(a)R^(h), —R^(f)C(═O)R^(h), —NR^(h)C(═O)R^(f),—NR^(h)C(═O)NR^(a)R^(f), —NR^(f)C(═O)NR^(a)R^(h), —NR^(h)CO₂R^(e),—NR^(f)CO₂R^(h), —C₁₋₈alkylOR^(h), —C₁₋₆alkylNR^(a)R^(h),—S(═O)_(n)R^(h), —S(═O)₂NR^(a)R^(h), —NR^(a)S(═O)₂R^(h),—NR^(h)S(═O)₂R^(e), —OS(═O)₂R^(h) and —OC(═O)NR^(a)R^(h).

In another embodiment, in conjunction with any one of the above andbelow embodiments, at least one of wherein at least one of R⁵, R⁶, R⁷,R⁸ and R⁹ is R^(e), R^(h), halo, nitro, cyano, —NR^(a)R^(f),—NR^(a)R^(h), —NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f),naphthyl, —CO₂R^(e), —C(═O)R^(e), —OC(═O)R^(e), —C(═O)NR^(a)R^(f),—C(═O)NR^(a)R^(h), —NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(e),—NR^(f)C(═O)NR^(a)R, —NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f),—C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f),—NR^(a)S(═O)₂R^(e), —OS(═O)₂R^(e), —OC(═O)NR^(a)R^(f), —OR^(h),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(n), —NR^(a)R^(h),—NR^(f)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(f)C₂₋₆alkylOR^(f), —NR^(f)C₂₋₆alkylOR^(h), —CO₂R^(h), —OC(═O)R^(h),—C(═O)R^(h), —C(═O)NR^(a)R^(h), —NR^(f)C(═O)R^(h), —NR^(h)C(═O)R^(f),—NR^(h)C(═O)NR^(a)R^(f), —NR^(f)C(═O)NR^(a)R^(h), —NR^(h)CO₂R^(e),—NR^(f)CO₂R^(h), —C₁₋₈alkylOR^(h), —C₁₋₆alkylNR^(a)R^(h), —S(═O)R^(h),—S(═O)₂NR^(a)R^(h), —NR^(a)S(═O)₂R^(h), —NR^(h)S(═O)₂R^(e),—OS(═O)₂R^(h) or —OC(═O)NR^(a)R^(h).

In another embodiment, in conjunction with any one of the above andbelow embodiments, at least one of R⁵, R⁶, R⁷, R⁸ and R⁹ is tert-butylor CF₃.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹⁰ is independently, at each instance, selected fromH, C₁₋₅alkyl, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —C(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(h),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹⁰ is a saturated or unsaturated 5-, 6- or7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclicring containing 1, 2 or 3 atoms selected from N, O and S, wherein thereare no more than 2 N atoms, and wherein the ring is fused with 0 or 1benzo groups and 0 or 1 saturated or unsaturated 5-, 6- or 7-memberedheterocyclic ring containing 1, 2 or 3 atoms selected from N, O and S;wherein the ring is substituted by 0, 1 or 2 oxo or thioxo groups,wherein the ring is substituted by 0, 1, 2 or 3 groups selected fromC₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(e),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹⁰ is C₁₋₄alkyl substituted by 0, 1, 2 or 3groups selected from C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e) —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h).

Embodiment M: In another embodiment, in conjunction with any one of theabove and below embodiments, R¹⁰ is H.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹⁰ is independently, at each instance, selected fromC₁₋₅ alkyl, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹⁰ is a saturated or unsaturated 5-, 6- or7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclicring containing 1, 2 or 3 atoms selected from N, O and S, wherein thereare no more than 2 N atoms, and wherein the ring is fused with 0 or 1benzo groups and 0 or 1 saturated or unsaturated 5-, 6- or 7-memberedheterocyclic ring containing 1, 2 or 3 atoms selected from N, O and S;wherein the ring is substituted by 0, 1 or 2 oxo or thioxo groups,wherein the ring is substituted by 0, 1, 2 or 3 groups selected fromC₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂NR^(h)C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹⁰ is C₁₋₄alkyl substituted by 0, 1, 2 or 3groups selected from C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(l), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(h),—N(R^(a))S(═O)₂R^(e), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹¹ is independently, at each instance, selected fromH, C₁₋₈alkyl, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(l), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹¹ is a saturated or unsaturated 5-, 6- or7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclicring containing 1, 2 or 3 atoms selected from N, O and S, wherein thering is fused with 0 or 1 benzo groups and 0 or 1 saturated orunsaturated 5-, 6- or 7-membered heterocyclic ring containing 1, 2 or 3atoms selected from N, O and S; wherein the ring is substituted by 0, 1or 2 oxo or thioxo groups, wherein the ring is substituted by 0, 1, 2 or3 groups selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro,—C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f),—OR^(f), —OC(═O)R³, —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(l), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹¹ is C₁₋₄alkyl substituted by 0, 1, 2 or 3groups selected from C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹⁰ and R¹¹ together are a saturated orunsaturated 3-, 4- or 5-atom bridge containing 1, 2 or 3 atoms selectedfrom O, N and S with the remaining atoms being carbon, so long as thecombination of O and S atoms is not greater than 2, wherein the bridgeis substituted by 0, 1 or 2 substituents selected from oxo, thioxo,R^(c), R^(e), halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(f), —N(R^(a))S(═O)₂NR^(a)R^(h),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(f), —C(═O)NR^(a)R, —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹⁰ and R¹¹ together are a saturated orpartially unsaturated 3-, 4- or 5-carbon bridge, wherein the bridge issubstituted by 0, 1 or 2 substituents selected from oxo, thioxo, R^(c),R^(e), halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); and when R¹⁰ and R¹¹ together form a bridge, R¹²may additionally be halo or —CF₃, R¹³ may additionally be halo or—OR^(a) or cyano or nitro, and R¹⁴ may additionally be halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹¹ is independently, at each instance, selected fromC₁₋₈alkyl, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR, —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹¹ is a saturated or unsaturated 5-, 6- or7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclicring containing 1, 2 or 3 atoms selected from N, O and S, wherein thering is fused with 0 or 1 benzo groups and 0 or 1 saturated orunsaturated 5-, 6- or 7-membered heterocyclic ring containing 1, 2 or 3atoms selected from N, O and S; wherein the ring is substituted by 0, 1or 2 oxo or thioxo groups, wherein the ring is substituted by 0, 1, 2 or3 groups selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro,—C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f),—OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a) C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(e), —N(R^(h))C(═O)R^(h), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R^(h) is C₁₋₄alkyl substituted by 0, 1, 2 or3 groups selected from C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e) —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and —NR^(a)C₂₋₆alkylOR^(h);or R¹⁰ and R¹¹ together are a saturated or unsaturated 3-, 4- or 5-atombridge containing 1, 2 or 3 atoms selected from O, N and S with theremaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2, wherein the bridge is substituted by 0, 1or 2 substituents selected from oxo, thioxo, R^(c), R^(e), halo, cyano,nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(e))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹⁰ and R¹¹ together are a saturated orpartially unsaturated 3-, 4- or 5-carbon bridge, wherein the bridge issubstituted by 0, 1 or 2 substituents selected from oxo, thioxo, R^(c),R^(e), halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); and when R¹⁰ and R¹¹ together form a bridge, R¹²may additionally be halo or —CF₃, R¹³ may additionally be halo or—OR^(a) or cyano or nitro, and R¹⁴ may additionally be halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹¹ is independently, at each instance, selected fromC₁₋₈alkyl, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)R^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and —NR^(a)C₂₋₆alkylOR^(h).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹¹ is a saturated or unsaturated 5-, 6- or7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclicring containing 1, 2 or 3 atoms selected from N, O and S, wherein thering is fused with 0 or 1 benzo groups and 0 or 1 saturated orunsaturated 5-, 6- or 7-membered heterocyclic ring containing 1, 2 or 3atoms selected from N, O and S; wherein the ring is substituted by 0, 1or 2 oxo or thioxo groups, wherein the ring is substituted by 0, 1, 2 or3 groups selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro,—C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f),—OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR¹¹, —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹¹ is C₁₋₄alkyl substituted by 0, 1, 2 or 3 groupsselected from C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h).

Embodiment N: In another embodiment, in conjunction with any one of theabove and below embodiments, R¹⁰ and R¹¹ together are a saturated orunsaturated 3-, 4- or 5-atom bridge containing 1, 2 or 3 atoms selectedfrom O, N and S with the remaining atoms being carbon, so long as thecombination of O and S atoms is not greater than 2, wherein the bridgeis substituted by 0, 1 or 2 substituents selected from oxo, thioxo,R^(c), R^(e), halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h)—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); and when R¹⁰ and R¹¹ together form a bridge, R¹²may additionally be halo or —CF₃, R¹³ may additionally be halo or—OR^(a) or cyano or nitro, and R¹⁴ may additionally be halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹⁰ and R¹¹ together are a saturated or unsaturated3-atom bridge containing 1, 2 or 3 atoms selected from O, N and S withthe remaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2, wherein the bridge is substituted by 0, 1or 2 substituents selected from oxo, thioxo, R^(c), R^(e), halo, cyano,nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); and when R¹⁰ and R¹¹ together form a bridge, R¹²may additionally be halo or —CF₃, R¹³ may additionally be halo or—OR^(a) or cyano or nitro, and R¹⁴ may additionally be halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹⁰ and R¹¹ together are a saturated or unsaturated4-atom bridge containing 1, 2 or 3 atoms selected from O, N and S withthe remaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2, wherein the bridge is substituted by 0, 1or 2 substituents selected from oxo, thioxo, R^(c), R^(e), halo, cyano,nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(l), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); and when R¹⁰ and R¹¹ together form a bridge, R¹²may additionally be halo or —CF₃, R¹³ may additionally be halo or—OR^(a) or cyano or nitro, and R¹⁴ may additionally be halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹⁰ and R¹¹ together are a saturated or unsaturated3-, 4- or 5-atom bridge containing 1, 2 or 3 atoms selected from O, Nand S with the remaining atoms being carbon, so long as the combinationof O and S atoms is not greater than 2, wherein the bridge issubstituted by 1 or 2 substituents selected from R^(c), R^(e), halo,cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(h),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(f), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); and when R¹⁰ and R¹¹ together form a bridge, R¹²may additionally be halo or —CF₃, R¹³ may additionally be halo or—OR^(a) or cyano or nitro, and R¹⁴ may additionally be halo.

Embodiment O: In another embodiment, in conjunction with any one of theabove and below embodiments, R¹⁰ and R¹¹ together are a saturated orunsaturated 3-atom bridge containing 1 or 2 atoms selected from O, N andS with the remaining atoms being carbon, wherein the bridge issubstituted by 1 or 2 substituents selected from R^(c), R^(e), halo,cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(e))C(═O)R^(h),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); and when R¹⁰ and R¹¹ together form a bridge, R¹²may additionally be halo or —CF₃, R¹³ may additionally be halo or—OR^(a) or cyano or nitro, and R¹⁴ may additionally be halo.

Embodiment P: In another embodiment, in conjunction with any one of theabove and below embodiments, R¹⁰ and R¹¹ together are a saturated orunsaturated 3-atom bridge containing 1 or 2 atoms selected from O, N andS with the remaining atoms being carbon, wherein the bridge issubstituted by a substituents selected from R^(c), R^(e), —C(═O)R^(e),—C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(Ph)C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h)—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); and the bridge is additionally substituted by 0or 1 substituents selected from R^(e), oxo, thioxo, halo, cyano, nitro,—C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f),—OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h)—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(e))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(h)C₂₋₆alkylOR^(h); and when R¹⁰ and R¹¹ together form a bridge, R¹²may additionally be halo or —CF₃, R¹³ may additionally be halo or—OR^(a) or cyano or nitro, and R¹⁴ may additionally be halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹⁰ and R¹¹ together are a saturated or unsaturated3-atom bridge containing 1 or 2 atoms selected from O, N and S with theremaining atoms being carbon, wherein the bridge is substituted by asubstituents selected from —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); and when R¹⁰ and R¹¹ together form a bridge, R¹²may additionally be halo or —CF₃, R¹³ may additionally be halo or—OR^(a) or cyano or nitro, and R¹⁴ may additionally be halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, or R¹⁰ and R¹¹ together are a saturated or partiallyunsaturated 3-, 4- or 5-carbon bridge, wherein the bridge is substitutedby 0, 1 or 2 substituents selected from oxo, thioxo, R^(c), R^(e), halo,cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹² is independently, at each instance, selected fromH, C₁₋₈alkyl, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹² is a saturated or unsaturated 5-, 6- or7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclicring containing 1, 2 or 3 atoms selected from N, O and S, wherein thering is fused with 0 or 1 benzo groups and 0 or 1 saturated orunsaturated 5-, 6- or 7-membered heterocyclic ring containing 1, 2 or 3atoms selected from N, O and S; wherein the ring is substituted by 0, 1or 2 oxo or thioxo groups, wherein the ring is substituted by 0, 1, 2 or3 groups selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro,—C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f),—OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹² is C₁₋₄alkyl substituted by 0, 1, 2 or 3groups selected from C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h), and additionally substituted by 0, 1 or 2 halogroups; or R¹¹ and R¹² together are a saturated or unsaturated 3-, 4- or5-atom bridge containing 1, 2 or 3 atoms selected from O, N and S withthe remaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2, wherein the bridge is substituted by 0, 1or 2 substituents selected from oxo, thioxo, R^(c), R^(e), halo, cyano,nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R,—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(l), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); wherein when R³ is NH₂, then —R¹¹—R¹²— is not—C═C—C═N— or any substituted version thereof, or R¹¹ and R¹² togetherare a saturated or partially unsaturated 3-, 4- or 5-carbon bridge,wherein the bridge is substituted by 0, 1 or 2 substituents selectedfrom oxo, thioxo, R^(c), R^(e), halo, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(e), —N(R^(e))C(═O)NR^(a)R,—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(h),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); and when R¹¹ and R¹² together form a bridge, R¹⁰may additionally be halo, R¹³ may additionally be halo or —OR^(a) orcyano or nitro, and R¹⁴ may additionally be halo.

Embodiment Q: In another embodiment, in conjunction with any one of theabove and below embodiments, R¹² is H.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹² is independently, at each instance, selected fromC₁₋₈alkyl, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹² is a saturated or unsaturated 5-, 6- or7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclicring containing 1, 2 or 3 atoms selected from N, O and S, wherein thering is fused with 0 or 1 benzo groups and 0 or 1 saturated orunsaturated 5-, 6- or 7-membered heterocyclic ring containing 1, 2 or 3atoms selected from N, O and S; wherein the ring is substituted by 0, 1or 2 oxo or thioxo groups, wherein the ring is substituted by 0, 1, 2 or3 groups selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro,—C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f),—OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a) R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹² is C₁₋₄alkyl substituted by 0, 1, 2 or 3groups selected from C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h), and additionally substituted by 0, 1 or 2 halogroups; or R¹¹ and R¹² together are a saturated or unsaturated 3-, 4- or5-atom bridge containing 1, 2 or 3 atoms selected from O, N and S withthe remaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2, wherein the bridge is substituted by 0, 1or 2 substituents selected from oxo, thioxo, R^(c), R^(e), halo, cyano,nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); wherein when R³ is NH₂, then R¹¹R¹² is not—C═C—C═N— or any substituted version thereof; or R¹¹ and R¹² togetherare a saturated or partially unsaturated 3-, 4- or 5-carbon bridge,wherein the bridge is substituted by 0, 1 or 2 substituents selectedfrom oxo, thioxo, R^(c), R^(e), halo, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); and when R¹¹ and R¹² together form a bridge, R¹⁰may additionally be halo, R¹³ may additionally be halo or —OR^(a) orcyano or nitro, and R¹⁴ may additionally be halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹² is a saturated or unsaturated 5-, 6- or7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclicring containing 1, 2 or 3 atoms selected from N, O and S, wherein thering is fused with 0 or 1 benzo groups and 0 or 1 saturated orunsaturated 5-, 6- or 7-membered heterocyclic ring containing 1, 2 or 3atoms selected from N, O and S; wherein the ring is substituted by 0, 1or 2 oxo or thioxo groups, wherein the ring is substituted by 0, 1, 2 or3 groups selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro,—C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f),—OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹¹ and R¹² together are a saturated or unsaturated3-, 4- or 5-atom bridge containing 1, 2 or 3 atoms selected from O, Nand S with the remaining atoms being carbon, so long as the combinationof O and S atoms is not greater than 2, wherein the bridge issubstituted by 0, 1 or 2 substituents selected from oxo, thioxo, R^(c),R^(e), halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); wherein R¹¹R¹²is not —C(NH₂)═C—C═N— or anysubstituted version thereof; or R¹¹ and R¹² together are a saturated orpartially unsaturated 3-, 4- or 5-carbon bridge, wherein the bridge issubstituted by 0, 1 or 2 substituents selected from oxo, thioxo, R^(c),R^(e), halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(l), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h)—NR^(h)C₂₋₆alkylOR^(f)nd—NR^(a)C₂₋₆alkylOR^(h); and when R¹¹ and R¹² together form a bridge, R¹⁰may additionally be halo, R¹³ may additionally be halo or —OR^(a) orcyano or nitro, and R¹⁴ may additionally be halo.

Embodiment R: In another embodiment, in conjunction with any one of theabove and below embodiments, R¹¹ and R¹² together are a saturated orunsaturated 3-, 4- or 5-atom bridge containing 1, 2 or 3 atoms selectedfrom O, N and S with the remaining atoms being carbon, so long as thecombination of O and S atoms is not greater than 2, wherein the bridgeis substituted by 0, 1 or 2 substituents selected from oxo, thioxo,R^(c), R^(e), halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(a)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); wherein when R³ is NH₂, then R¹¹R¹² is not—C═C—C═N— or any substituted version thereof, and when R¹¹ and R¹²together form a bridge, R¹⁰ may additionally be halo, R¹³ mayadditionally be halo or —OR^(a) or cyano or nitro, and R¹⁴ mayadditionally be halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹¹ and R¹² together are a saturated or unsaturated3-, 4- or -atom bridge containing 1, 2 or 3 atoms selected from O, N andS with the remaining atoms being carbon, so long as the combination of Oand S atoms is not greater than 2, and for a 4-atom bridge the firstattachment atom in R¹² is not N, wherein the bridge is substituted by 0,1 or 2 substituents selected from oxo, thioxo, R^(c), R^(e), halo,cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and —NR^(a)C₂₋₆alkylOR^(h);wherein when R³ is NH₂, then R¹¹R¹² is not —C═C—C═N— or any substitutedversion thereof; and when R¹¹ and R¹² together form a bridge, R¹⁰ mayadditionally be halo, R¹³ may additionally be halo or —OR^(a) or cyanoor nitro, and R¹⁴ may additionally be halo.

Embodiment S: In another embodiment, in conjunction with any one of theabove and below embodiments, R¹¹ and R¹² together are a saturated orunsaturated 3-atom bridge containing 1, 2 or 3 atoms selected from O, Nand S with the remaining atoms being carbon, so long as the combinationof O and S atoms is not greater than 2, wherein the bridge issubstituted by 0, 1 or 2 substituents selected from oxo, thioxo, R^(c),R^(e), halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); and when R¹¹ and R¹² together form a bridge, R¹⁰may additionally be halo, R¹³ may additionally be halo or —OR^(a) orcyano or nitro, and R¹⁴ may additionally be halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹¹ and R¹² together are a saturated or unsaturated3-atom bridge containing 1 or 2 atoms selected from O, N and S with theremaining atoms being carbon, wherein the bridge is substituted by 0, 1or 2 substituents selected from oxo, thioxo, R^(c), R^(e), halo, cyano,nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h),N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); and when R¹¹ and R¹² together form a bridge, R¹⁰may additionally be halo, R¹³ may additionally be halo or —OR^(a) orcyano or nitro, and R¹⁴ may additionally be halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹¹ and R¹² together are a saturated or unsaturated3-atom bridge containing 1 or 2 atoms selected from O, N and S with theremaining atoms being carbon, wherein the bridge is substituted by 1 or2 substituents selected from oxo, thioxo, R^(c), R^(e), halo, cyano,nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); and when R¹¹ and R¹² together form a bridge, R¹⁰may additionally be halo, R¹³ may additionally be halo or —OR^(a) orcyano or nitro, and R¹⁴ may additionally be halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹¹ and R¹² together are a saturated or unsaturated3-atom bridge containing 1 or 2 atoms selected from O, N and S with theremaining atoms being carbon, wherein the bridge is substituted byR^(e), R^(c), —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR, —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(f), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(e), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); and when R¹¹ and R¹² together form a bridge, R¹⁰may additionally be halo, R¹³ may additionally be halo or OR^(a) orcyano or nitro, and R¹⁴ may additionally be halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹¹ and R¹² together are a saturated or unsaturated3-atom bridge containing 1 or 2 atoms selected from O, N and S with theremaining atoms being carbon, wherein the bridge is substituted by—C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f),—OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NRaf,—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₅alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(l), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂A(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(l),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(e))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(e))S(═O)₂NR^(a)R,—N(R^(a))S(═O)₂NR^(a)R^(l), —NR^(h)C₂₋₆alkyNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(a)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); and when R¹¹ and R¹² together form a bridge, R¹⁰may additionally be halo, R¹³ may additionally be halo or —OR^(a) orcyano or nitro, and R¹⁴ may additionally be halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹¹ and R¹² together are a saturated or unsaturated4-atom bridge containing 1, 2 or 3 atoms selected from O, N and S withthe remaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2 and first attachment atom in R¹² is not N,wherein the bridge is substituted by 0, 1 or 2 substituents selectedfrom oxo, thioxo, R^(c), R^(e), halo, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(h), —OR^(f),—OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(f), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₅alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); and when R¹¹ and R¹² together form a bridge, R¹⁰may additionally be halo, R¹³ may additionally be halo or —OR^(a) orcyano or nitro, and R¹⁴ may additionally be halo.

Embodiment T: In another embodiment, in conjunction with any one of theabove and below embodiments, R¹¹ and R¹² together form a —R¹¹—R¹²—bridge selected from —O—C≡C—O—, —N—C≡C—C— and —N═C—C═C—, wherein thebridge is substituted by 0, 1 or 2 substituents selected from oxo,thioxo, R^(c), R^(e), halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R, —OR^(f), —C(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(h), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h),—C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h),—OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC(═O)N(R^(e))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(e), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(l),—S(═O)₂N(R^(e))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h)—NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R, —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f)an-NR^(a)C₂₋₆alkylOR^(f) and when R¹¹ and R¹² together form a bridge,R¹⁰ may additionally be halo, R¹³ may additionally be halo or —OR^(a) orcyano or nitro, and R¹⁴ may additionally be halo.

R¹¹ and R¹² together form a —R¹¹—R¹²— bridge selected from —O—C—C—O—,—N—C—C—C— and —N═C—C═C—, wherein the bridge is substituted by 1 or 2substituents selected from oxo, thioxo, R^(c), R^(e), halo, cyano,nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R, —NR^(a)C₂₋₆alkylNR^(a)R, —NR^(a)C₂₋₆alkylOR^(f),—C(═O)R^(h), —C(═O)OR^(e), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h),—OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R¹)C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R, —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(e))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h) —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); and when R¹¹ and R¹² together form a bridge, R¹⁰may additionally be halo, R¹³ may additionally be halo or —OR^(a) orcyano or nitro, and R¹⁴ may additionally be halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, or R¹⁰ and R¹¹ together are a saturated or partiallyunsaturated 3-, 4- or 5-carbon bridge, wherein the bridge is substitutedby 0, 1 or 2 substituents selected from oxo, thioxo, R^(c), R^(e), halo,cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(h)C(═O)NR^(a)R^(h), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R, —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹³ is independently, at each instance, selected fromH, C₁₋₈alkyl, —C(═O)R^(e), —C(═O)OR, —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R, —OR, —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R,—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(e))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R, —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and —NR^(a)C₂₋₆alkylOR^(h); or R¹³ is a saturated or unsaturated 5-, 6- or7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclicring containing 1, 2 or 3 atoms selected from N, O and S, wherein thering is fused with 0 or 1 benzo groups and 0 or 1 saturated orunsaturated 5-, 6- or 7-membered heterocyclic ring containing 1, 2 or 3atoms selected from N, O and S; wherein the ring is substituted by 0, 1or 2 oxo or thioxo groups, wherein the ring is substituted by 0, 1, 2 or3 groups selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro,—C(═O)_(k)W, —C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f),—OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R, —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R,—N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a) C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R¹¹, —C(═O)OR^(h), —C(═O)NR^(a)R,—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkyNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹³ is C₁₋₄alkyl substituted by 0, 1, 2 or 3groups selected from C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e) —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), c(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(e)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹³ is H.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹³ is independently, at each instance, selected fromC₁₋₈alkyl, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR, —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(h), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)NR^(a)R^(f) —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(e), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(l), —N(R^(e))C(═O)R^(e),—N(R^(a))C(O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(l),—N(R^(h))C(═NR^(a))NR^(a)R, —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(e))S(═O)₂R^(e), —N(a)S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹³ is a saturated or unsaturated 5-, 6- or7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclicring containing 1, 2 or 3 atoms selected from N, O and S, wherein thering is fused with 0 or 1 benzo groups and 0 or 1 saturated orunsaturated 5-, 6- or 7-membered heterocyclic ring containing 1, 2 or 3atoms selected from N, O and S; wherein the ring is substituted by 0, 1or 2 oxo or thioxo groups, wherein the ring is substituted by 0, 1, 2 or3 groups selected from C₁₋₈alkyl, C₄haloalkyl, halo, cyano, nitro,—C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f),—OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR,—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R, —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(e), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R,—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R,—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹³ is C₁₋₄alkyl substituted by 0, 1, 2 or 3 groupsselected from C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(e))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(h),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NE^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹⁴ is independently, at each instance, selected fromH, C₁₋₅alkyl, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹⁴ is a saturated or unsaturated 5-, 6- or7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclicring containing 1, 2 or 3 atoms selected from N, O and S, wherein thereare no more than 2 N atoms, and wherein the ring is fused with 0 or 1benzo groups and 0 or 1 saturated or unsaturated 5-, 6- or 7-memberedheterocyclic ring containing 1, 2 or 3 atoms selected from N, O and S;wherein the ring is substituted by 0, 1 or 2 oxo or thioxo groups,wherein the ring is substituted by 0, 1, 2 or 3 groups selected fromC₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(h),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C_(2,6)alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and —NR^(a)C₂₋₆alkylOR^(h);or R¹⁴ is C₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylN^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —Nr^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹⁴ is H.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹⁴ is independently, at each instance, selected fromC₁₋₅alkyl, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkyNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹⁴ is a saturated or unsaturated 5-, 6- or7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclicring containing 1, 2 or 3 atoms selected from N, O and S, wherein thereare no more than 2 N atoms, and wherein the ring is fused with 0 or 1benzo groups and 0 or 1 saturated or unsaturated 5-, 6- or 7-memberedheterocyclic ring containing 1, 2 or 3 atoms selected from N, O and S;wherein the ring is substituted by 0, 1 or 2 oxo or thioxo groups,wherein the ring is substituted by 0, 1, 2 or 3 groups selected fromC₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(l), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f)and—NR^(a)C₂₋₆alkylOR^(h); or R¹⁻⁴ is Cl₁₋₄alkyl substituted by 0, 1, 2 or3 groups selected from C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h).

In another embodiment, in conjunction with any one of the above andbelow embodiments, at least one of R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ is otherthan H.

In another embodiment, in conjunction with any one of the above andbelow embodiments, at least two of R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ is otherthan H.

In another embodiment, in conjunction with any one of the above andbelow embodiments, at least one of R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ isselected from C₁₋₅ alkyl, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR_(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and —NR^(a)C₂₋₆alkylOR^(h), or a saturated or unsaturated 5-, 6- or 7-memberedmonocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S, wherein there areno more than 2 N atoms, and wherein the ring is fused with 0 or 1 benzogroups and 0 or 1 saturated or unsaturated 5-, 6- or 7-memberedheterocyclic ring containing 1, 2 or 3 atoms selected from N, O and S;wherein the ring is substituted by 0, 1 or 2 oxo or thioxo groups,wherein the ring is substituted by 0, 1, 2 or 3 groups selected fromC₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and —NR^(a)C₂₋₆alkylOR^(h);or a C₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂NR^(a)C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(l), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylONR^(a)R^(h), —NR^(h)C₁₋₂alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h)

In another embodiment, in conjunction with any one of the above andbelow embodiments, R^(b) is a heterocycle selected from the group ofthiophene, pyrrole, 1,3-oxazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole,1,2,3-oxadiazole, 1,2,3-thiadiazole, 1H-1,2,3-triazole, isothiazole,1,2,4-oxadiazole, 1,2,4-thiadiazole, 1,2,3,4-oxatriazole,1,2,3,4-thiatriazole, 1H-1,2,3,4-tetraazole, 1,2,3,5-oxatriazole,1,2,3,5-thiatriazole, furan, imidazol-2-yl, benzimidazole,1,2,4-triazole, isoxazole, thiolane, pyrrolidine, tetrahydrofuran,4,5-dihydrothiophene, 2-pyrroline, 4,5-dihydrofuran, pyridazine,pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine,pyridine, 2H-3,4,5,6-tetrahydropyran, thiane, 1,2-diazaperhydroine,1,3-diazaperhydroine, piperazine, 1,3-oxazaperhydroine, morpholine,1,3-thiazaperhydroine, 1,4-thiazaperhydroine, piperidine,2H-3,4-dihydropyran, 2,3-dihydro-4H-thiin, 1,4,5,6-tetrahydropyridine,2H-5,6-dihydropyran, 2,3-dihydro-6H-thiin, 1,2,5,6-tetrahydropyridine,3,4,5,6-tetrahydropyridine, 4H-pyran, 4H-thiin, 1,4-dihydropyridine,1,4-dithiane, 1,4-dioxane, 1,4-oxathiane, 1,2-oxazolidine,1,2-thiazolidine, pyrazolidine, 1,3-oxazolidine, 1,3-thiazolidine,imidazolidine, 1,2,4-oxadiazolidine, 1,3,4-oxadiazolidine,1,2,4-thiadiazolidine, 1,3,4-thiadiazolidine, 1,2,4-triazolidine,2-imidazolin-1-yl, 2-imidazolin-2-yl, 3-imidazoline, 2-pyrazoline,4-imidazoline, 2,3-dihydroisothiazole, 4,5-dihydroisoxazole,4,5-dihydroisothiazole, 2,5-dihydroisoxazole, 2,5-dihydroisothiazole,2,3-dihydroisoxazole, 4,5-dihydrooxazole, 2,3-dihydrooxazole,2,5-dihydrooxazole, 4,5-dihydrothiazole, 2,3-dihydrothiazole,2,5-dihydrothiazole, 1,3,4-oxathiazolidine, 1,4,2-oxathiazolidine,2,3-dihydro-1H-[1,2,3]triazole, 2,5-dihydro-1H-[1,2,3]triazole,4,5-dihydro-1H-[1,2,3]triazol-1-yl, 4,5-dihydro-1H-[1,2,3]triazol-3-yl,4,5-dihydro-1H-[1,2,3]triazol-5-yl, 2,3-dihydro-1H-[1,2,4]triazole,4,5-dihydro-1H-[1,2,4]triazole, 2,3-dihydro-[1,2,4]oxadiazole,2,5-dihydro-[1,2,4]oxadiazole, 4,5-dihydro-[1,2,4]thiadiazole,2,3-dihydro-[1,2,4]thiadiazole, 2,5-dihydro-[1,2,4]thiadiazole,4,5-dihydro-[1,2,4]thiadiazole, 2,5-dihydro-[1,2,4]oxadiazole,2,3-dihydro-[1,2,4]oxadiazole, 4,5-dihydro-[1,2,4]oxadiazole,2,5-dihydro-[1,2,4]thiadiazole, 2,3-dihydro-[1,2,4]thiadiazole,4,5-dihydro-[1,2,4]thiadiazole, 2,3-dihydro-[1,3,4]oxadiazole,2,3-dihydro-[1,3,4]thiadiazole, [1,4,2]oxathiazole, [1,3,4]oxathiazole,1,3,5-triazaperhydroine, 1,2,4-triazaperhydroine,1,4,2-dithiazaperhydroine, 1,4,2-dioxazaperhydroine,1,3,5-oxadiazaperhydroine, 1,2,5-oxadiazaperhydroine,1,3,4-thiadiazaperhydroine, 1,3,5-thiadiazaperhydroine,1,2,5-thiadiazaperhydroine, 1,3,4-oxadiazaperhydroine,1,4,3-oxathiazaperhydroine, 1,4,2-oxathiazaperhydroine,1,4,5,6-tetrahydropyridazine, 1,2,3,4-tetrahydropyridazine,1,2,3,6-tetrahydropyridazine, 1,2,5,6-tetrahydropyrimidine,1,2,3,4-tetrahydropyrimidine, 1,4,5,6-tetrahydropyrimidine,1,2,3,6-tetrahydropyrazine, 1,2,3,4-tetrahydropyrazine,5,6-dihydro-4H-[1,2]oxazine, 5,6-dihydro-2H-[1,2]oxazine,3,6-dihydro-2H-[1,2]oxazine, 3,4-dihydro-2H-[1,2]oxazine,5,6-dihydro-4H-[1,2]thiazine, 5,6-dihydro-2H-[1,2] thiazine,3,6-dihydro-21H-[1,2]thiazine, 3,4-dihydro-2H-[1,2] thiazine,5,6-dihydro-2H-[1,3]oxazine, 5,6-dihydro-4H-[1,3]oxazine,3,6-dihydro-2H-[1,3]oxazine, 3,4-dihydro-2H-[1,3]oxazine,3,6-dihydro-21H-[1,4]oxazine, 3,4-dihydro-2H-[1,4]oxazine,5,6-dihydro-2H-[1,3]thiazine, 5,6-dihydro-4H-[1,3]thiazine,3,6-dihydro-2H-[1,3]thiazine, 3,4-dihydro-2H-[1,3]thiazine,3,6-dihydro-2H-[1,4]thiazine, 3,4-dihydro-2H-[1,4]thiazine,1,2,3,6-tetrahydro-[1,2,4]triazine, 1,2,3,4-tetrahydro-[1,2,4]triazine,1,2,3,4-tetrahydro-[1,3,5]triazine, 2,3,4,5-tetrahydro-[1,2,4]triazine,1,4,5,6-tetrahydro-[1,2,4]triazine, 5,6-dihydro-[1,4,2]dioxazine,5,6-dihydro-[1,4,2]dithiazine, 2,3-dihydro-[1,4,2]dioxazine,3,4-dihydro-2H-[1,3,4]oxadiazine, 3,6-dihydro-2H-[1,3,4]oxadiazine,3,4-dihydro-2H-[1,3,5]oxadiazine, 3,6-dihydro-2H-[1,3,5]oxadiazine,5,6-dihydro-2H-[1,2,5]oxadiazine, 5,6-dihydro-4H-[1,2,5]oxadiazine,3,4-dihydro-2H-[1,3,4]thiadiazine, 3,6-dihydro-2H-[1,3,4]thiadiazine,3,4-dihydro-2H-[1,3,5]thiadiazine, 3,6-dihydro-2H-[1,3,5]thiadiazine,5,6-dihydro-2H-[1,2,5]thiadiazine, 5,6-dihydro-4H-[1,2,5]thiadiazine,5,6-dihydro-2H-[1,2,3]oxadiazine, 3,6-dihydro-2H-[1,2,5]oxadiazine,5,6-dihydro-4H-[1,3,4]oxadiazine, 3,4-dihydro-2H-[1,2,5]oxadiazine,5,6-dihydro-2H-[1,2,3]thiadiazine, 3,6-dihydro-2H-[1,2,5]thiadiazine,5,6-dihydro-4H-[1,3,4]thiadiazine, 3,4-dihydro-2H-[1,2,5]thiadiazine,5,6-dihydro-[1,4,3]oxathiazine, 5,6-dihydro-[1,4,2]oxathiazine,2,3-dihydro-[1,4,3]oxathiazine, 2,3-dihydro-[1,4,2]oxathiazine,3,4-dihydropyridine, 1,2-dihydropyridine, 5,6-dihydropyridine, 2H-pyran,2H-thiin, 3,6-dihydropyridine, 2,3-dihydropyridazine,2,5-dihydropyridazine, 4,5-dihydropyridazine, 1,2-dihydropyridazine,1,4-dihydropyrimidin-1-yl, 1,4-dihydropyrimidin-4-yl,1,4-dihydropyrimidin-5-yl, 1,4-dihydropyrimidin-6-yl,2,3-dihydropyrimidine, 2,5-dihydropyrimidine, 5,6-dihydropyrimidine,3,6-dihydropyrimidine, 5,6-dihydropyrazine, 3,6-dihydropyrazine,4,5-dihydropyrazine, 1,4-dihydropyrazine, 1,4-dithiin, 1,4-dioxin,2H-1,2-oxazine, 6H-1,2-oxazine, 4H-1,2-oxazine, 2H-1,3-oxazine,4H-1,3-oxazine, 6H-1,3-oxazine, 2H-1,4-oxazine, 4H-1,4-oxazine,2H-1,3-thiazine, 2H-1,4-thiazine, 4H-1,2-thiazine, 6H-1,3-thiazine,4H-1,4-thiazine, 2H-1,2-thiazine, 6H-1,2-thiazine, 1,4-oxathiin,2H,5H-1,2,3-triazine, 1H,4H-1,2,3-triazine, 4,5-dihydro-1,2,3-triazine,1H,6H-1,2,3-triazine, 1,2-dihydro-1,2,3-triazine,2,3-dihydro-1,2,4-triazine, 3H,6H-1,2,4-triazine, 1H,6H-1,2,4-triazine,3,4-dihydro-1,2,4-triazine, 1H,4H-1,2,4-triazine,5,6-dihydro-1,2,4-triazine, 4,5-dihydro-1,2,4-triazine,2H,5H-1,2,4-triazine, 1,2-dihydro-1,2,4-triazine, 1H,4H-1,3,5-triazine,1,2-dihydro-1,3,5-triazine, 1,4,2-dithiazine, 1,4,2-dioxazine,2H-1,3,4-oxadiazine, 2H-1,3,5-oxadiazine, 6H-1,2,5-oxadiazine,4H-1,3,4-oxadiazine, 4H-1,3,5-oxadiazine, 4H-1,2,5-oxadiazine,2H-1,3,5-thiadiazine, 6H-1,2,5-thiadiazine, 4H-1,3,4-thiadiazine,4H-1,3,5-thiadiazine, 4H-1,2,5-thiadiazine, 2H-1,3,4-thiadiazine,6H-1,3,4-thiadiazine, 6H-1,3,4-oxadiazine, and 1,4,2-oxathiazine,wherein the heterocycle is optionally vicinally fused with a saturatedor unsaturated 5-, 6- or 7-membered ring containing 0, 1 or 2 atomsindependently selected from N, O and S.

In another embodiment, the compound is selected from:

(2R)-2-hydroxy-N-[4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]propanamide;

(2S)-2-hydroxy-N-[4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]propanamide;

(2S)-3-[2-[6-(quinolin-7-yloxy)pyrimidin-4-yl]-5-(trifluoromethyl)phenoxy]propane-1,2-diol;

[7-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinolin-3-yl]methanol;

1-[7-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinolin-3-yl]ethanol;

1-methyl-5-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;

2-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoline;

2-(4-methyl-1,4-diazepan-1-yl)-4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazole;

2-(6-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}pyrimidin-4-yl)-5-(trifluoromethyl)phenyltrifluoromethanesulfonate;

2-[6-(quinolin-7-yloxy)pyrimidin-4-yl]-5-(trifluoromethyl)aniline;

2-[6-(quinolin-7-yloxy)pyrimidin-4-yl]-5-(trifluoromethyl)phenol;

2-[6-(quinolin-7-yloxy)pyrimidin-4-yl]phenol;

2-[7-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinolin-3-yl]propan-2-ol;

2-{6-[(2-amino-1,3-benzothiazol-4-yl)oxy]pyrimidin-4-yl}-5-(trifluoromethyl)phenol;

2-bromo-4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazole;

2-chloro-4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazole;

2-chloro-7-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoline;

2-chloro-8-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoline;

2-hydroxy-2-methyl-N-[4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]propanamide;

2-hydroxy-2-phenyl-N-[4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;

2-hydroxy-N-[4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]propanamide;

2-hydroxy-N-[4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;

2-iodo-4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazole;

2-methyl-5-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazole;

2-methyl-5-({6-phenyl-5-[4-(trifluoromethyl)phenyl]pyridazin-3-yl}oxy)-1,3-benzothiazole;

2-methyl-8-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxaline;

2-morpholin-4-yl-N-[4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;

2-phenyl-N-[4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;

2-pyridin-4-yl-4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazole;

3-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)isoquinoline;

3-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)pyridin-2-amine;

3-amino-5-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2(1H)-one;

4-({6-[2-(methoxymethoxy)-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;

4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;

4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazole;

4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazole-2,6-diamine;

4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazole-2-carboxamide;

4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzoxazol-2-amine;

4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)isoquinoline;

4-({6-[4-(trifluoromethyl)piperidin-1-yl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;

4-(1-benzothien-4-yloxy)-6-[4-(trifluoromethyl)phenyl]pyrimidine;

4-(2,3-dihydro-1,4-benzodioxin-6-yloxy)-6-[4-(trifluoromethyl)phenyl]pyrimidine;

4-(2-naphthyloxy)-6-[4-(trifluoromethyl)phenyl]pyrimidine;

4-(2-pyridin-2-ylethoxy)-6-[4-(trifluoromethyl)phenyl]pyrimidine;

4-(3-methoxyphenoxy)-6-[4-(trifluoromethyl)phenyl]pyrimidine;

4-(4-tert-butylphenyl)-6-(3-methoxyphenoxy)pyrimidine;

4-(4-tert-butylphenyl)-6-(quinolin-7-yloxy)pyrimidin-2-amine;

4-[(6-{4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}pyrimidin-4-yl)oxy]-1,3-benzothiazol-2-amine;

4-[6-(quinolin-7-yloxy)pyrimidin-4-yl]benzonitrile;

4-{[6-(2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)pyrimidin-4-yl]oxy}-1,3-benzothiazol-2-amine;

4-{[6-(4-bromophenyl)pyrimidin-4-yl]oxy}-1,3-benzothiazol-2-amine;

4-{[6-(4-cycloheptylpiperazin-1-yl)pyrimidin-4-yl]oxy}-1,3-benzothiazol-2-amine;

4-{[6-(4-phenylpiperazin-1-yl)pyrimidin-4-yl]oxy}-1,3-benzothiazol-2-amine;

4-{6-[(2-aminoquinolin-8-yl)oxy]pyrimidin-4-yl}benzonitrile;

4-chloro-7-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoline;

4-methyl-8-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoline;

5-({5,6-bis[4-(trifluoromethyl)phenyl]pyridazin-3-yl}oxy)-2-methyl-1,3-benzothiazole;

5-({6-(isoquinolin-5-yloxy)-4-[4-(trifluoromethyl)phenyl]pyridazin-3-yl}oxy)isoquinoline;

5-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-3,4-dihydroquinoxalin-2(1H)-one;

5-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)isoquinoline;

5-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoline;

5-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2-ol;

5-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2-amine;

5-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxaline;

5-{[6-(4-tert-butylphenyl)pyrimidin-4-yl]oxy}-2-methyl-1,3-benzothiazole;

6-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1H-indole;

6-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)isoquinoline;

6-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxaline;

7-({6-(2-naphthyl)-5-[4-(trifluoromethyl)phenyl]pyridazin-3-yl}oxy)quinoline;

7-({6-(3-fluorophenyl)-5-[4-(trifluoromethyl)phenyl]pyridazin-3-yl}oxy)quinoline;

7-({6-(4-fluorophenyl)-5-[4-(trifluoromethyl)phenyl]pyridazin-3-yl}oxy)quinoline;

7-({6-(isoquinolin-7-yloxy)-4-[4-(trifluoromethyl)phenyl]pyridazin-3-yl}oxy)isoquinoline;

7-({6-(quinolin-7-yloxy)-4-[4-(trifluoromethyl)phenyl]pyridazin-3-yl}oxy)quinoline;

7-({6-[2-(benzyloxy)-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoline;

7-({6-[2-(cyclohexylmethoxy)-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoline;

7-({6-[2-(methoxymethoxy)-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoline;

7-({6-[2,4-bis(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoline;

7-({6-[2-bromo-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoline;

7-({6-[2-chloro-6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl}oxy)quinoline;

7-({6-[2-piperidin-1-yl-6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl}oxy)quinoline;

7-({6-[2-pyridin-3-yl-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoline;

7-({6-[3-(methylsulfanyl)phenyl]pyrimidin-4-yl}oxy)quinoline;

7-({6-[3-(trifluoromethoxy)phenyl]pyrimidin-4-yl}oxy)quinoline;

7-({6-[4-(trifluoromethoxy)phenyl]-5-[4-(trifluoromethyl)phenyl]pyridazin-3-yl}oxy)quinoline;

7-({6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl}oxy)quinoline;

7-({6-[4-(trifluoromethyl)-2-vinylphenyl]pyrimidin-4-yl}oxy)quinoline;

7-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-3,4-dihydronaphthalen-1(2H)-one;

7-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)isoquinoline;

7-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinolin-2-amine;

7-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinolin-2-ol;

7-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoline;

7-({6-[4′-fluoro-5-(trifluoromethyl)-1,1′-biphenyl-2-yl]pyrimidin-4-yl}oxy)quinoline;

7-({6-[5-(trifluoromethyl)-1,1′-biphenyl-2-yl]pyrimidin-4-yl}oxy)quinoline;

7-({6-phenyl-5-[4-(trifluoromethyl)phenyl]pyridazin-3-yl}oxy)quinoline;

7-[(6-phenylpyrimidin-4-yl)oxy]quinoline;

7-{[6-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)pyrimidin-4-yl]oxy}quinoline;

7-{[6-(1-benzofuran-5-yl)pyrimidin-4-yl]oxy}quinoline;

7-{[6-(1-methyl-1H-indol-5-yl)pyrimidin-4-yl]oxy}quinoline;

7-{[6-(2,4-dichlorophenyl)pyrimidin-4-yl]oxy}quinoline;

7-{[6-(2-naphthyl)pyrimidin-4-yl]oxy}quinoline;

7-{[6-(3,4-difluorophenyl)pyrimidin-4-yl]oxy}quinoline;

7-{[6-(3-chloro-4-fluorophenyl)pyrimidin-4-yl]oxy}quinoline;

7-{[6-(3-fluoro-4-methylphenyl)pyrimidin-4-yl]oxy}quinoline;

7-{[6-(3-nitrophenyl)pyrimidin-4-yl]oxy}quinoline;

7-{[6-(3-piperidin-1-ylphenyl)pyrimidin-4-yl]oxy}quinoline;

7-{[6-(3-pyrrolidin-1-ylphenyl)pyrimidin-4-yl]oxy}quinoline;

7-{[6-(4-bromophenyl)pyrimidin-4-yl]oxy}quinoline;

7-{[6-(4-chlorophenyl)pyrimidin-4-yl]oxy}quinoline;

7-{[6-(4-fluorophenyl)pyrimidin-4-yl]oxy}quinoline;

7-{[6-(4-tert-butylphenyl)pyrimidin-4-yl]oxy}quinoline;

7-{[6-(6-chloropyridin-3-yl)pyrimidin-4-yl]oxy}quinoline;

7-{[6-(6-methoxypyridin-3-yl)pyrimidin-4-yl]oxy}quinoline;

7-pyridin-4-yl-4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;

8-({6-[2-amino-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinolin-2-amine;

8-({6-[3-(trifluoromethoxy)phenyl]pyrimidin-4-yl}oxy)quinolin-2-amine;

8-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-3,4-dihydroquinoxalin-2(1H)-one;

8-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)imidazo[1,2-a]pyridine;

8-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)isoquinoline;

8-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinazolin-2-amine;

8-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoline;

8-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2-amine;

8-({6-phenyl-5-[4-(trifluoromethyl)phenyl]pyridazin-3-yl}oxy)quinolin-2-amine;

8-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinolin-2-ylamine;

methyl2-(6-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}pyrimidin-4-yl)-5-(trifluoromethyl)benzoate;

methyl4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-ylcarbamate;

methyl7-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoline-3-carboxylate;

N-(4-{[6-(2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)pyrimidin-4-yl]oxy}-1,3-benzothiazol-2-yl)acetamide;

N-(4-{[6-(3-phenylpyrrolidin-1-yl)pyrimidin-4-yl]oxy}-1,3-benzothiazol-2-yl)acetamide;

N-(4-{[6-(4-benzylpiperazin-1-yl)pyrimidin-4-yl]oxy}-1,3-benzothiazol-2-yl)acetamide;

N-(4-{[6-(4-bromophenyl)pyrimidin-4-yl]oxy}-1,3-benzothiazol-2-yl)acetamide;

N-(4-{[6-(4-phenylpiperazin-1-yl)pyrimidin-4-yl]oxyl}-1,3-benzothiazol-2-yl)acetamide;

N-(4-{[6-(4-phenylpiperidin-1-yl)pyrimidin-4-yl]oxy}-1,3-benzothiazol-2-yl)acetamide;

N-(4-tert-butylbenzyl)-N-[2-[6-(quinolin-7-yloxy)pyrimidin-4-yl]-5-(trifluoromethyl)phenyl]amine;

N-(cyclohexylmethyl)-3-[6-(quinolin-7-yloxy)pyrimidin-4-yl]-6-(trifluoromethyl)pyridin-2-amine;

N-(cyclohexylmethyl)-N-[2-[6-(quinolin-7-yloxy)pyrimidin-4-yl]-5-(trifluoromethyl)phenyl]amine;

N-(pyridin-4-ylmethyl)-N-[2-[6-(quinolin-7-yloxy)pyrimidin-4-yl]-5-(trifluoromethyl)phenyl]amine;

N,N-dimethyl-4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazole-2-carboxamide;

N-[2-(6-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}pyrimidin-4-yl)-5-(trifluoromethyl)phenyl]cyclohexanecarboxamide;

N-[2-(6-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}pyrimidin-4-yl)-5-(trifluoromethyl)phenyl]-4-(trifluoromethyl)benzamide;

N-[2-(6-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}pyrimidin-4-yl)-5-(trifluoromethyl)phenyl]-2,2-dimethylpropanamide;

N-[2-(6-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}pyrimidin-4-yl)-5-(trifluoromethyl)phenyl]-2-cyclohexylacetamide;

N-[2-(6-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}pyrimidin-4-yl)-5-(trifluoromethyl)phenyl]nicotinamide;

N-[2-(6-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}pyrimidin-4-yl)-5-(trifluoromethyl)phenyl]isonicotinamide;

N-[2-(6-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}pyrimidin-4-yl)-5-(trifluoromethyl)phenyl]acetamide;

N-[2-[6-(quinolin-7-yloxy)pyrimidin-4-yl]-5-(trifluoromethyl)phenyl]benzenesulfonamide;

N-[2-[6-(quinolin-7-yloxy)pyrimidin-4-yl]-5-(trifluoromethyl)phenyl]acetamide;

N-[2-[6-(quinolin-7-yloxy)pyrimidin-4-yl]-5-(trifluoromethyl)phenyl]methanesulfonamide;

N-[3-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)phenyl]acetamide;

N-[4-({5-(4-fluorophenyl)-4-[4-(trifluoromethyl)phenyl]pyridin-2-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;

N-[4-({5-[4-(trifluoromethoxy)phenyl]-4-[4-(trifluoromethyl)phenyl]pyridin-2-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;

N-[4-({5-bromo-4-[4-(trifluoromethyl)phenyl]pyridin-2-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;

N-[4-({5-chloro-4-[4-(trifluoromethyl)phenyl]pyridin-2-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;

N-[4-({6-[2-(benzyloxy)-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;

N-[4-({6-[2-(hydroxymethyl)-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;

N-[4-({6-[2-(methoxymethoxy)-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;

N-[4-({6-[2-[(cyclohexylmethyl)amino]-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;

N-[4-({6-[2-[(piperidin-4-ylmethyl)amino]-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzoxazol-2-yl]acetamide;

N-[4-({6-[2-amino-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;

N-[4-({6-[2-bromo-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;

N-[4-({6-[2-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;

N-[4-({6-[2-hydroxy-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;

N-[4-({6-[2-iodo-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;

N-[4-({6-[4-(1-phenylethyl)piperazin-1-yl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;

N-[4-({6-[4-(2,6-dimethylphenyl)piperazin-1-yl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;

N-[4-({6-[4-(trifluoromethyl)-2-vinylphenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;

N-[4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;

N-[4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzoxazol-2-yl]acetamide;

N-[4-({6-phenyl-5-[4-(trifluoromethyl)phenyl]pyridazin-3-yl}oxy)-1,3-benzothiazol-2-yl]aczetamide;

N-[6-(dimethylamino)-4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;

N-[8-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinolin-2-yl]acetamide;

N-[8-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinoxalin-2-yl]acetamide;

N-{4-[(6-{4-[2-(trifluoromethyl)phenyl]piperazin-1-yl}pyrimidin-4-yl)oxy]-1,3-benzothiazol-2-yl}acetamide;

N-{4-[(6-{4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}pyrimidin-4-yl)oxy]-1,3-benzothiazol-2-yl}acetamide;

N˜2˜,N˜2˜-dimethyl-N˜1˜-[4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]glycinamide;

N-benzyl-N-[2-[6-(quinolin-7-yloxy)pyrimidin-4-yl]-5-(trifluoromethyl)phenyl]amine;

N-butyl-8-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinazolin-4-amine;

N-methyl-4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;

N-methyl-8-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)quinolin-2-amine;

N-pentyl-N-[2-[6-(quinolin-7-yloxy)pyrimidin-4-yl]-5-(trifluoromethyl)phenyl]amine;

N-pyridin-2-yl-4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-amine;

tert-butyl2-(6-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}pyrimidin-4-yl)-5-(trifluoromethyl)phenylcarbamate;

tert-butyl2-[6-(quinolin-7-yloxy)pyrimidin-4-yl]-5-(trifluoromethyl)phenylcarbamate;

tert-butyl2-{6-[(2-aminoquinolin-8-yl)oxy]pyrimidin-4-yl}-5-(trifluoromethyl)phenylcarbamate;

tert-butyl4-({[2-(6-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}pyrimidin-4-yl)-5-(trifluoromethyl)phenyl]amino}methyl)piperidine-1-carboxylate;

tert-butyl4-(6-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}pyrimidin-4-yl)piperazine-1-carboxylate;and

tert-butyl4-(6-{[2-(acetylamino)-1,3-benzothiazol-4-yl]oxy}pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate, or any pharmaceutically-acceptable salt thereof.

As stated above, the above embodiments may be used in conjuction withother embodiments listed. The following table is a non-exclusive,non-limiting list of some of the combinations of embodiments. Althoughthe following embodiment sets are meant to be used with any of the aboveembodiments, they are also considered wherein R⁵, R⁶, R⁸, R¹³ and R¹⁴are all H.

Where X is N and Y is CH:

Emb. # R¹ R⁴ R⁷ R⁹ R¹⁰ R¹¹ R¹² 1001 C E — — N N Q 1002 C E — — O O Q1003 C E — — P P Q 1004 C E — — M R R 1005 C E — — M S S 1006 C E — — MT T 1007 C D — — — — — 1008 C F — — — — — 1009 C G — — — — — 1010 A E HJ N N Q 1011 A E H J O O Q 1012 A E H J P P Q 1013 A E H J M R R 1014 AE H J M S S 1015 A E H J M T T 1016 A D H J — — — 1017 A F H J — — —1018 A G H J — — — 1019 A E H K N N Q 1020 A E H K O O Q 1021 A E H K PP Q 1022 A E H K M R R 1023 A E H K M S S 1024 A E H K M T T 1025 A D HK — — — 1026 A F H K — — — 1027 A G H K — — — 1028 A E H L N N Q 1029 AE H L O O Q 1030 A E H L P P Q 1031 A E H L M R R 1032 A E H L M S S1033 A E H L M T T 1034 A D H L — — — 1035 A F H L — — — 1036 A G H L —— — 1037 A E I J N N Q 1038 A E I J O O Q 1039 A E I J P P Q 1040 A E IJ M R R 1041 A E I J M S S 1042 A E I J M T T 1043 A D I J — — — 1044 AF I J — — — 1045 A G I J — — — 1046 A E I K N N Q 1047 A E I K O O Q1048 A E I K P P Q 1049 A E I K M R R 1050 A E I K M S S 1051 A E I K MT T 1052 A D I K — — — 1053 A F I K — — — 1054 A G I K — — — 1055 A E IL N N Q 1056 A E I L O O Q 1057 A E I L P P Q 1058 A E I L M R R 1059 AE I L M S S 1060 A E I L M T T 1061 A D I L — — — 1062 A F I L — — —1063 A G I L — — — 1064 B E H J N N Q 1065 B E H J O O Q 1066 B E H J PP Q 1067 B E H J M R R 1068 B E H J M S S 1069 B E H J M T T 1070 B D HJ — — — 1071 B F H J — — — 1072 B G H J — — — 1073 B E H K N N Q 1074 BE H K O O Q 1075 B E H K P P Q 1076 B E H K M R R 1077 B E H K M S S1078 B E H K M T T 1079 B D H K — — — 1080 B F H K — — — 1081 B G H K —— — 1082 B E H L N N Q 1083 B E H L O O Q 1084 B E H L P P Q 1085 B E HL M R R 1086 B E H L M S S 1087 B E H L M T T 1088 B D H L — — — 1089 BF H L — — — 1090 B G H L — — — 1091 B E I J N N Q 1092 B E I J O O Q1093 B E I J P P Q 1094 B E I J M R R 1095 B E I J M S S 1096 B E I J MT T 1097 B D I J — — — 1098 B F I J — — — 1099 B G I J — — — 1100 B E IK N N Q 1101 B E I K O O Q 1102 B E I K P P Q 1103 B E I K M R R 1104 BE I K M S S 1105 B E I K M T T 1106 B D I K — — — 1107 B F I K — — —1108 B G I K — — — 1109 B E I L N N Q 1110 B E I L O O Q 1111 B E I L PP Q 1112 B E I L M R R 1113 B E I L M S S 1114 B E I L M T T 1115 B D IL — — — 1116 B F I L — — — 1117 B G I L — — —where X is CH and Y is N:

Emb. # R¹ R⁴ R⁷ R⁹ R¹⁰ R¹¹ R¹² 2001 C E — — N N Q 2002 C E — — O O Q2003 C E — — P P Q 2004 C E — — M R R 2005 C E — — M S S 2006 C E — — MT T 2007 C D — — — — — 2008 C F — — — — — 2009 C G — — — — — 2010 A E HJ N N Q 2011 A E H J O O Q 2012 A E H J P P Q 2013 A E H J M R R 2014 AE H J M S S 2015 A E H J M T T 2016 A D H J — — — 2017 A F H J — — —2018 A G H J — — — 2019 A E H K N N Q 2020 A E H K O O Q 2021 A E H K PP Q 2022 A E H K M R R 2023 A E H K M S S 2024 A E H K M T T 2025 A D HK — — — 2026 A F H K — — — 2027 A G H K — — — 2028 A E H L N N Q 2029 AE H L O O Q 2030 A E H L P P Q 2031 A E H L M R R 2032 A E H L M S S2033 A E H L M T T 2034 A D H L — — — 2035 A F H L — — — 2036 A G H L —— — 2037 A E I J N N Q 2038 A E I J O O Q 2039 A E I J P P Q 2040 A E IJ M R R 2041 A E I J M S S 2042 A E I J M T T 2043 A D I J — — — 2044 AF I J — — — 2045 A G I J — — — 2046 A E I K N N Q 2047 A E I K O O Q2048 A E I K P P Q 2049 A E I K M R R 2050 A E I K M S S 2051 A E I K MT T 2052 A D I K — — — 2053 A F I K — — — 2054 A G I K — — — 2055 A E IL N N Q 2056 A E I L O O Q 2057 A E I L P P Q 2058 A E I L M R R 2059 AE I L M S S 2060 A E I L M T T 2061 A D I L — — — 2062 A F I L — — —2063 A G I L — — — 2064 B E H J N N Q 2065 B E H J O O Q 2066 B E H J PP Q 2067 B E H J M R R 2068 B E H J M S S 2069 B E H J M T T 2070 B D HJ — — — 2071 B F H J — — — 2072 B G H J — — — 2073 B E H K N N Q 2074 BE H K O O Q 2075 B E H K P P Q 2076 B E H K M R R 2077 B E H K M S S2078 B E H K M T T 2079 B D H K — — — 2080 B F H K — — — 2081 B G H K —— — 2082 B E H L N N Q 2083 B E H L O O Q 2084 B E H L P P Q 2085 B E HL M R R 2086 B E H L M S S 2087 B E H L M T T 2088 B D H L — — — 2089 BF H L — — — 2090 B G H L — — — 2091 B E I J N N Q 2092 B E I J O O Q2093 B E I J P P Q 2094 B E I J M R R 2095 B E I J M S S 2096 B E I J MT T 2097 B D I J — — — 2098 B F I J — — — 2099 B G I J — — — 2100 B E IK N N Q 2101 B E I K O O Q 2102 B E I K P P Q 2103 B E I K M R R 2104 BE I K M S S 2105 B E I K M T T 2106 B D I K — — — 2107 B F I K — — —2108 B G I K — — — 2109 B E I L N N Q 2110 B E I L O O Q 2111 B E I L PP Q 2112 B E I L M R R 2113 B E I L M S S 2114 B E I L M T T 2115 B D IL — — — 2116 B F I L — — — 2117 B G I L — — —

One aspect of the current invention relates to compounds having thegeneral structure:

or any pharmaceutically-acceptable salt thereof, wherein:

X is C(R²) and Y is C(R³); or X is N and Y is C(R³); or X is C(R²) and Yis N;

J is O or S;

n is independently, at each instance, 0, 1 or 2.

R¹ is

or R¹ is a naphthyl substituted by 0, 1, 2 or 3 substituentsindependently selected from R⁵; or R¹ is R^(b) substituted by 1, 2 or 3substituents independently selected from R⁵;

R² is, independently, in each instance, R¹⁰, C₁₋₈alkyl substituted by 0,1 or 2 substituents selected from R¹⁰, —(CH₂)_(n)phenyl wherein thephenyl is substituted by 0, 1, 2 or 3 substituents independentlyselected from R¹⁰, or a saturated or unsaturated 5- or 6-membered ringheterocycle containing 1, 2 or 3 heteroatoms independently selected fromN, O and S that is optionally vicinally fused with a saturated orunsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selectedfrom O, N and S with the remaining atoms being carbon, so long as thecombination of O and S atoms is not greater than 2, the heterocycle andbridge being substituted by 0, 1, 2 or 3 substituents independentlyselected from R¹⁰;

R³ is, independently, in each instance, H, halo, —NH₂, —NHC₁₋₃alkyl,—N(C₁₋₃alkyl)C₁₋₃alkyl, —OC₁₋₃alkyl, —C₁₋₂haloalkyl, —OC₁₋₂haloalkyl orC₁₋₃alkyl;

R⁴ is

wherein when R¹ is bromophenyl, methylphenyl or trifluoromethylphenyl,R⁴ is not trifluoromethylphenyl or trifluoromethylhalophenyl; or R⁴ is asaturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S, so long as the combination of Oand S atoms is not greater than 2, wherein each of the carbon atoms ofthe heterocycle is substituted by H, C₁₋₉alkyl, C₁₋₄haloalkyl, halo,cyano, oxo, —OR^(a), —S(═O)_(n)C₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkyNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —OC₁₋₆alkylC(═O)OR^(a),—NR^(a)R^(a), —NR^(a)C₁₋₄haloalkyl, —NR^(a) C₂₋₆alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or —NR^(a)C(═O)C₁₋₆alkyl; andunsaturated carbon atoms may be additionally substituted by ═O; and eachof the nitrogen atoms in the heterocycle are substituted by H,—C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —C₁₋₆alkyNR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(c)or —C₁₋₃alkylR^(c); or R⁴ is an 8-, 9-, 10- or 11-membered bicyclicring, containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selectedfrom S and O with the remainder being carbon atoms, wherein each of thecarbon atoms of the ring is substituted by H, C₁₋₉alkyl, C₁₋₄haloalkyl,halo, cyano, oxo, —OR^(a), —S(═O)_(n)C₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —OC₁₋₆alkylC(═O)OR^(a),—NR^(a)R^(a), —NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂-alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or —NR^(a)C(═O)C₁₋₆alkyl; andunsaturated carbon atoms may be additionally substituted by ═O; and anyavailable nitrogen atoms in the ring are substituted by H,—C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(O)NR^(a)R^(a),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(c)or —C₁₋₃alkylR^(c);

R⁵ is independently, at each instance, H, C₁₋₅alkyl, C₁₋₄haloalkyl,halo, nitro, —OC₁₋₆ alkyl, —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —NR^(a)R^(a), —NR^(a)C₁₋₄haloalkyl,—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), naphthyl,—CO₂(C₁₋₆alkyl), —C(═O)(C₁₋₆alkyl), —C(═O)NR^(a)R^(a),—NR^(a)C(═O)R^(a), —NR^(a)C(═O)NR^(a)R^(a), —NR^(a)CO₂(C₁₋₆alkyl),—C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a), —S(═O)_(n)(C₁₋₆alkyl),—S(═O)₂NR^(a)R^(a), —NR^(a)S(═O)₂(C₁₋₆alkyl), —OC(═O)NR^(a)R^(a), aphenyl ring substituted with 0, 1, 2, or 3 substituents independentlyselected from R¹⁰; or R⁵ is a saturated or unsaturated 5- or 6-memberedring heterocycle containing 1, 2 or 3 atoms selected from O, N and S,substituted with 0, 1, 2, or 3 substituents independently selected fromR¹⁰;

R⁶ is independently, at each instance, H, C₁₋₅alkyl, C₁₋₄haloalkyl,halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl, —OC₂₋₆alkyl NR^(a)R^(a),—NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a) or—NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈a OR^(a), —C₁₋₆alkylNR^(a)R^(a),—S(C₁₋₆alkyl), a phenyl ring substituted with 1, 2, or 3 substituentsindependently selected from R¹⁰; or R⁶ is a saturated or unsaturated 5-or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected fromO, N and S substituted with 0, 1, 2, or 3 substituents independentlyselected from R¹⁰;

R⁷ is independently, at each instance, H, C₁₋₈alkyl, C₁₋₄haloalkyl,bromo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —NR^(a)R^(a), —NR^(a)C₁₋₄haloalkyl,—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a),—C₁₋₆alkylNR^(a)R^(a) or —S(C₁₋₆alkyl); or R⁷ is a saturated orunsaturated 4- or 5-membered ring heterocycle containing a singlenitrogen atom, wherein the ring is substituted with 0, 1 or 2substituents independently selected from halo, C₁₋₂haloalkyl andC₁₋₃alkyl;

R⁸ is independently, at each instance, H, C₁₋₅alkyl, C₁₋₄haloalkyl,halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —NR^(a)R^(a), —NR^(a)C₁₋₄ haloalkyl,—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a),—C₆alkylNR^(a)R^(a), —S(C₁₋₆alkyl), a phenyl ring substituted with 1, 2,or 3 substituents independently selected from R¹⁰, or R⁸ is a saturatedor unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3atoms selected from O, N and S substituted with 0, 1, 2, or 3substituents independently selected from R¹⁰;

R⁹ is independently, at each instance, H, C₁₋₈alkyl, C₁₋₄haloalkyl,halo, nitro, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —NR^(a)R^(a), —NR^(a)C₁₋₄ haloalkyl,—NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a), —CO₂(C₁₋₆alkyl),—C(═O)(C₁₋₆alkyl), —C(═O)NR^(a)R^(a), —NR^(a)C(═O)(C₁₋₆alkyl),—NR^(a)C(═O)NR^(a)R^(a), —NR^(a)CO₂(C₁₋₆alkyl), —C₁₋₈alkylOR^(a),—C₁₋₆alkylNR^(a)R^(a), —S(═O)_(n)(C₁₋₆alkyl), —S(═O)₂NR^(a)R^(a),—NR^(a)S(═O)₂(C₁₋₆alkyl), —OC(═O)NR^(a)R^(a), a phenyl ring substitutedwith 0, 1, 2, or 3 substituents independently selected from R¹⁰; or R⁹is a saturated or unsaturated 5- or 6-membered ring heterocyclecontaining 1, 2 or 3 atoms selected from O, N and S substituted with 0,1, 2, or 3 substituents independently selected from R¹⁰; wherein atleast one of R⁵, R⁶, R⁷, R⁸ and R⁹ is C₁₋₈alkyl, C₁₋₄haloalkyl, halo,—OC₁₋₄haloalkyl, —R⁹ is C₁₋₈alkyl, C₁₋₄haloalkyl, halo, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)C₁₋₄haloalkyl—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a),—C₁₋₈alkylNR^(a)R^(a) or —S(C₁₋₆alkyl); or R⁹ is a saturated orunsaturated 4- or 5-membered ring heterocycle containing a singlenitrogen atom, wherein the ring is substituted with 0, 1 or 2substituents independently selected from halo, C₁₋₂haloalkyl andC₁₋₃alkyl;

R¹⁰ is independently, at each instance, selected from H, C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁰ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1 or 2 atoms selectedfrom N, O and S that is optionally vicinally fused with a saturated orunsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selectedfrom O, N and S with the remaining atoms being carbon, so long as thecombination of O and S atoms is not greater than 2, wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈ alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂(C18alkyl), —OC₂₋₆alkylNR^(a)R^(a)-OC₂₋₆alkylOR^(a), —SR^(a),—S(═O)(C₈alkyl), —S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁰ isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₄alkylOR^(a);

R¹¹ is independently, at each instance, selected from H, C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₄alkylNR^(a)R^(a), —OC₂alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹¹ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)(Cz8alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂(C₁₋₈alkyl),—N(R^(a))S(═O)₂NR^(a)R^(a), and —NR^(a)C₂₋₆alkylOR^(a); or R¹¹ is C₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected from C₁₋₄haloalkyl,halo, cyano, nitro, —C(═O)(C₁₋₈alkyl), —C(═O)O(C₁₋₈alkyl),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)(C₁₋₈alkyl),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆ alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl),—S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);

R¹² is independently, at each instance, selected from H, C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)O(C₁₋₈alkyl),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)(C₁₋₈alkyl),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl),—S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹² is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl) —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹² isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂alkylOR^(a);

R¹³ is independently, at each instance, selected from H, C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹³ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1, 2 or 3 atoms selectedfrom N, O and S, wherein the ring is fused with 0 or 1 benzo groups and0 or 1 saturated or unsaturated 5-, 6- or 7-membered heterocyclic ringcontaining 1, 2 or 3 atoms selected from N, O and S; wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a), and—NR^(a)C₂₋₆alkylOR^(a); or R¹³ is C₁₋₄alkyl substituted by 0, 1, 2 or 3groups selected from C₁₋₄haloalkyl, halo, cyano, nitro,—C(═O)(C₁₋₈alkyl), —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);

R¹⁴ is independently, at each instance, selected from H, C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylOR^(a), —SR^(a),—S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁴ is asaturated or unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-,9-, 10- or 11-membered bicyclic ring containing 1 or 2 atoms selectedfrom N, 0 and S that is optionally vicinally fused with a saturated orunsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selectedfrom O, N and S with the remaining atoms being carbon, so long as thecombination of O and S atoms is not greater than 2, wherein the carbonatoms of the ring are substituted by 0, 1 or 2 oxo groups, wherein thering is substituted by 0, 1, 2 or 3 groups selected from C₁₋₈ alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹⁴ isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);

R^(a) is independently, at each instance, H, phenyl, benzyl orC₁₋₆alkyl, the phenyl, benzyl and C₁₋₆alkyl being substituted by 0, 1, 2or 3 substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl,—OC₁₋₄alkyl, —NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C₁₋₄alkyl;

R^(b) is a heterocycle selected from the group of thiophene, pyrrole,1,3-oxazole, 1,3-thiazol-5-yl, 1,3,4-oxadiazole, 1,3,4-thiadiazole,1,2,3-oxadiazole, 1,2,3-thiadiazole, 1H-1,2,3-triazole, isothiazole,1,2,4-oxadiazole, 1,2,4-thiadiazole, 1,2,3,4-oxatriazole,1,2,3,4-thiatriazole, 1H-1,2,3,4-tetraazole, 1,2,3,5-oxatriazole,1,2,3,5-thiatriazole, furan, imidazol-1-yl, imidazol-3-yl,imidazol-4-yl, 1,2,4-triazole, 1,2,4-triazole, isoxazole, pyrazol-3-yl,pyrazol-4-yl, pyrazol-5-yl, thiolane, pyrrolidine, tetrahydrofuran,4,5-dihydrothiophene, 2-pyrroline, 4,5-dihydrofuran, pyridazine,pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine,pyridine, 2H-3,4,5,6-tetrahydropyran, thiane, 1,2-diazaperhydroine,1,3-diazaperhydroine, piperazine, 1,3-oxazaperhydroine, morpholine,1,3-thiazaperhydroine, 1,4-thiazaperhydroine, piperidine,2H-3,4-dihydropyran, 2,3-dihydro-4H-thiin, 1,4,5,6-tetrahydropyridine,2H-5,6-dihydropyran, 2,3-dihydro-6H-thiin, 1,2,5,6-tetrahydropyridine,3,4,5,6-tetrahydropyridine, 4H-pyran, 4H-thiin, 1,4-dihydropyridine,1,4-dithiane, 1,4-dioxane, 1,4-oxathiane, 1,2-oxazolidine,1,2-thiazolidine, pyrazolidine, 1,3-oxazolidine, 1,3-thiazolidine,imidazolidine, 1,2,4-oxadiazolidine, 1,3,4-oxadiazolidine,1,2,4-thiadiazolidine, 1,3,4-thiadiazolidine, 1,2,4-triazolidine,2-imidazolin-1-yl, 2-imidazolin-2-yl, 2-imidazolin-5-yl, 3-imidazoline,2-pyrazoline, 4-imidazoline, 2,3-dihydroisothiazole,4,5-dihydroisoxazole, 4,5-dihydroisothiazole, 2,5-dihydroisoxazole,2,5-dihydroisothiazole, 2,3-dihydroisoxazole, 4,5-dihydrooxazole,2,3-dihydrooxazole, 2,5-dihydrooxazole, 4,5-dihydrothiazole,2,3-dihydrothiazole, 2,5-dihydrothiazole, 1,3,4-oxathiazolidine,1,4,2-oxathiazolidine, 2,3-dihydro-1 H-[1,2,3]triazole,2,5-dihydro-1H-[1,2,3]triazole, 4,5-dihydro-1H-[1,2,3]triazol-1-yl,4,5-dihydro-1H-[1,2,3]triazol-3-yl, 4,5-dihydro-1H-[1,2,3]triazol-5-yl,2,3-dihydro-1H-[1,2,4]triazole, 4,5-dihydro-1H-[1,2,4]triazole,2,3-dihydro-[1,2,4]oxadiazole, 2,5-dihydro-[1,2,4]oxadiazole,4,5-dihydro-[1,2,4]thiadiazole, 2,3-dihydro-[1,2,4] thiadiazole,2,5-dihydro-[1,2,4] thiadiazole, 4,5-dihydro-[1,2,4] thiadiazole,2,5-dihydro-[1,2,4]oxadiazole, 2,3-dihydro-[1,2,4]oxadiazole,4,5-dihydro-[1,2,4]oxadiazole, 2,5-dihydro-[1,2,4]thiadiazole,2,3-dihydro-[1,2,4] thiadiazole, 4,5-dihydro-[1,2,4] thiadiazole,2,3-dihydro-[1,3,4]oxadiazole, 2,3-dihydro-[1,3,4]thiadiazole,[1,4,2]oxathiazole, [1,3,4]oxathiazole, 1,3,5-triazaperhydroine,1,2,4-triazaperhydroine, 1,4,2-dithiazaperhydroine,1,4,2-dioxazaperhydroine, 1,3,5-oxadiazaperhydroine,1,2,5-oxadiazaperhydroine, 1,3,4-thiadiazaperhydroine,1,3,5-thiadiazaperhydroine, 1,2,5-thiadiazaperhydroine,1,3,4-oxadiazaperhydroine, 1,4,3-oxathiazaperhydroine,1,4,2-oxathiazaperhydroine, 1,4,5,6-tetrahydropyridazine,1,2,3,4-tetrahydropyridazine, 1,2,3,6-tetrahydropyridazine,1,2,5,6-tetrahydropyrimidine, 1,2,3,4-tetrahydropyrimidine,1,4,5,6-tetrahydropyrimidine, 1,2,3,6-tetrahydropyrazine,1,2,3,4-tetrahydropyrazine, 5,6-dihydro-4H-[1,2]oxazine,5,6-dihydro-2H-[1,2]oxazine, 3,6-dihydro-2H-[1,2]oxazine,3,4-dihydro-2H-[1,2]oxazine, 5,6-dihydro-4H-[1,2]thiazine,5,6-dihydro-2H-[1,2] thiazine, 3,6-dihydro-2H-[1,2] thiazine,3,4-dihydro-2H-[1,2] thiazine, 5,6-dihydro-2H-[1,3]oxazine,5,6-dihydro-4H-[1,3]oxazine, 3,6-dihydro-2H-[1,3]oxazine,3,4-dihydro-2H-[1,3]oxazine, 3,6-dihydro-2H-[1,4]oxazine,3,4-dihydro-2H-[1,4]oxazine, 5,6-dihydro-2H-[1,3]thiazine,5,6-dihydro-4H-[1,3]thiazine, 3,6-dihydro-2H-[1,3]thiazine,3,4-dihydro-2H-[1,3]thiazine, 3,6-dihydro-2H-[1,4]thiazine,3,4-dihydro-2H-[1,4]thiazine, 1,2,3,6-tetrahydro-[1,2,4]triazine,1,2,3,4-tetrahydro-[1,2,4]triazine, 1,2,3,4-tetrahydro-[1,3,5]triazine,2,3,4,5-tetrahydro-[1,2,4]triazine, 1,4,5,6-tetrahydro-[1,2,4]triazine,5,6-dihydro-[1,4,2]dioxazine, 5,6-dihydro-[1,4,2]dithiazine,2,3-dihydro-[1,4,2]dioxazine, 3,4-dihydro-2H-[1,3,4]oxadiazine,3,6-dihydro-2H-[1,3,4]oxadiazine, 3,4-dihydro-2H-[1,3,5]oxadiazine,3,6-dihydro-2H-[1,3,5]oxadiazine, 5,6-dihydro-2H-[1,2,5]oxadiazine,5,6-dihydro-4H-[1,2,5]oxadiazine, 3,4-dihydro-2H-[1,3,4]thiadiazine,3,6-dihydro-2H-[1,3,4]thiadiazine, 3,4-dihydro-2H-[1,3,5]thiadiazine,3,6-dihydro-2H-[1,3,5]thiadiazine, 5,6-dihydro-2H-[1,2,5]thiadiazine,5,6-dihydro-4H-[1,2,5]thiadiazine, 5,6-dihydro-2H-[1,2,3]oxadiazine,3,6-dihydro-2H-[1,2,5]oxadiazine, 5,6-dihydro-4H-[1,3,4]oxadiazine,3,4-dihydro-2H-[1,2,5]oxadiazine, 5,6-dihydro-2H-[1,2,3]thiadiazine,3,6-dihydro-2H-[1,2,5]thiadiazine, 5,6-dihydro-4H-[1,3,4]thiadiazine,3,4-dihydro-2H-[1,2,5]thiadiazine, 5,6-dihydro-[1,4,3]oxathiazine,5,6-dihydro-[1,4,2]oxathiazine, 2,3-dihydro-[1,4,3]oxathiazine,2,3-dihydro-[1,4,2]oxathiazine, 3,4-dihydropyridine,1,2-dihydropyridine, 5,6-dihydropyridine, 2H-pyran, 2H-thiin,3,6-dihydropyridine, 2,3-dihydropyridazine, 2,5-dihydropyridazine,4,5-dihydropyridazine, 1,2-dihydropyridazine, 1,4-dihydropyrimidin-1-yl,1,4-dihydropyrimidin-4-yl, 1,4-dihydropyrimidin-5-yl,1,4-dihydropyrimidin-6-yl, 2,3-dihydropyrimidine, 2,5-dihydropyrimidine,5,6-dihydropyrimidine, 3,6-dihydropyrimidine, 5,6-dihydropyrazine,3,6-dihydropyrazine, 4,5-dihydropyrazine, 1,4-dihydropyrazine,1,4-dithiin, 1,4-dioxin, 2H-1,2-oxazine, 6H-1,2-oxazine, 4H-1,2-oxazine,2H-1,3-oxazine 4H-1,3-oxazine, 6H-1,3-oxazine, 2H-1,4-oxazine,4H-1,4-oxazine, 2H-1,3-thiazine, 2H-1,4-thiazine, 4H-1,2-thiazine,6H-1,3-thiazine, 4H-1,4-thiazine, 2H-1,2-thiazine, 6H-1,2-thiazine,1,4-oxathiin, 2H,5H-1,2,3-triazine, 1H,4H-1,2,3-triazine,4,5-dihydro-1,2,3-triazine, 1H,6H-1,2,3-triazine,1,2-dihydro-1,2,3-triazine, 2,3-dihydro-1,2,4-triazine,3H,6H-1,2,4-triazine, 1H,6H-1,2,4-triazine, 3,4-dihydro-1,2,4-triazine,1H,4H-1,2,4-triazine, 5,6-dihydro-1,2,4-triazine,4,5-dihydro-1,2,4-triazine, 2H,5H-1,2,4-triazine,1,2-dihydro-1,2,4-triazine, 1H,4H-1,3,5-triazine,1,2-dihydro-1,3,5-triazine, 1,4,2-dithiazine, 1,4,2-dioxazine,2H-1,3,4-oxadiazine, 2H-1,3,5-oxadiazine, 6H-1,2,5-oxadiazine,4H-1,3,4-oxadiazine, 4H-1,3,5-oxadiazine, 4H-1,2,5-oxadiazine,2H-1,3,5-thiadiazine, 6H-1,2,5-thiadiazine, 4H-1,3,4-thiadiazine,4H-1,3,5-thiadiazine, 4H-1,2,5-thiadiazine, 2H-1,3,4-thiadiazine,6H-1,3,4-thiadiazine, 6H-1,3,4-oxadiazine, and 1,4,2-oxathiazine,wherein the heterocycle is optionally vicinally fused with a saturatedor unsaturated 5-, 6- or 7-membered ring containing 0, 1 or 2 atomsindependently selected from N, O and S;

R^(c) is phenyl substituted by 0, 1 or 2 groups selected from halo,C₁₋₄alkyl, C₁₋₃haloalkyl, —OR^(a) and —NR^(a)R^(a); or R^(C) is asaturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein nomore than 2 of the ring members are O or S, wherein the heterocycle isoptionally fused with a phenyl ring, and the carbon atoms of theheterocycle are substituted by 0, 1 or 2 oxo groups, wherein theheterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OR^(a) and—NR^(a)R^(a); and

R^(d) is independently in each instance hydrogen or —CH₃.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁷ is C₂₋₆alkyl or C₁₋₄ haloalkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is a naphthyl substituted by 0, 1, 2 or 3substituents independently selected from R⁵.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is R^(b) substituted by 1, 2 or 3 substituentsindependently selected from R⁵.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is 4-tert-butylphenyl or 4-trifluoromethylphenyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R^(b) is substituted by one substituent selected fromhalo, C₁₋₄haloalkyl and C₁₋₅alkyl, and additionally by 0, 1 or 2substituents independently selected from R⁵.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R² is H.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R² is R¹⁰, C₁₋₈alkyl substituted by 0, 1 or 2substituents selected from R¹⁰, or a saturated or unsaturated 5- or6-membered ring heterocycle containing 1, 2 or 3 heteroatomsindependently selected from N, O and S that is optionally vicinallyfused with a saturated or unsaturated 3- or 4-atom bridge containing 0,1, 2 or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of O and S atoms is not greater than2, the heterocycle and bridge being substituted by 0, 1, 2 or 3substituents independently selected from R¹⁰; or R² is —(CH₂)_(n)phenylsubstituted by 0, 1, 2 or 3 substituents independently selected from H,C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), C(═NR^(a))NR^(a)R^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈ alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), and C₁₋₄alkylsubstituted by 0, 1, 2 or 3 groups selected from C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)(C₁₋₈alkyl), —C(═O)O(C₈₋₁alkyl), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —C(=1)₈(C₁ alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R³ is H.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R³ is halo, —NHC₁₋₃alkyl, —N(C₁₋₃alkyl)C₁₋₃alkyl,—OC₁₋₃alkyl, —C₁₋₂haloalkyl, —OC₁₋₂haloalkyl or C₁₋₃alkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is

wherein at least one of R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ is other thanC₁₋₄haloalkyl or halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, at least one of R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ is —OR^(a)or —NR^(a)R^(a).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is a saturated or unsaturated 5- or 6-memberedring heterocycle containing 1, 2 or 3 atoms selected from O, N and S, solong as the combination of O and S atoms is not greater than 2, whereineach of the carbon atoms of the heterocycle is substituted by H,C₁₋₉alkyl, C₁₋₄haloalkyl, halo, cyano, oxo, OR^(a), —S(═O)_(n)C₁₋₆alkyl,—OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—OC₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a), —NR^(a)C₁₋₄haloalkyl,—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl,—C(═O)OC₁₋₆alkyl, —OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or—NR^(a)C(═O)C₁₋₆alkyl; and unsaturated carbon atoms may be additionallysubstituted by ═O; and any available nitrogen atoms in the heterocycleare substituted by H, —C₁₋₆alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(c)or —C₁₋₃alkylR^(c).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is a saturated or unsaturated 5- or 6-memberedring heterocycle containing 1 or 2 atoms selected from O, N and S,wherein each of the carbon atoms of the heterocycle is substituted by H,C₁₋₉alkyl, C₁₋₄haloalkyl, halo, cyano, oxo, —OR^(a), —S(═O).C lalkyl,—OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—OC₁₋₆alkylC(═O)O R^(a), —NR^(a)R^(a), —NR^(a)C₄haloalkyl,—NR^(a)C₂₋₆alkylNR^(a), —NR^(a)C₂₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl,—C(═O)OC₁₋₆alkyl, —OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or—NR^(a)C(═O)C₁₋₆alkyl; and unsaturated carbon atoms may be additionallysubstituted by ═O; and any available nitrogen atoms in the chain aresubstituted by H, —C₁₋₆alkylOR, —C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(a)C(═O)C₆alkyl, —C(═O)R^(c) or—C₁₋₃alkylR^(c).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is an 8-, 9-, 10- or 11-membered bicyclic ring,containing 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from S andO with the remainder being carbon atoms, wherein each of the carbonatoms of the ring is substituted by H, C₁₋₉alkyl, C₁₋₄haloalkyl, halo,cyano, oxo, —OR^(a), —S(═O),C₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₂₆alkylNR^(a), —OC₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a),—NR^(a)C₁₋₄haloalkyl, —NR^(a)C 26alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or —NR^(a)C(═O)C₁₋₆alkyl; andunsaturated carbon atoms may be additionally substituted by ═O; and anyavailable nitrogen atoms in the ring are substituted by H,—C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(C)or —C₁₋₃alkylR^(c).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is an 8-, 9-, 10- or 11-membered bicyclic ring,containing 1, 2, 3 or 4 N atoms with the remainder being carbon atoms,wherein each of the carbon atoms of the ring is substituted by H,C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, oxo, —OR^(a),—S(═O)_(n)C₁₋₆alkyl, —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a),—OC₂₋₆alkylOR^(a), —OC₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a),—NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂ alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or —NR^(a)C(═O)C₁₋₆alkyl; andunsaturated carbon atoms may be additionally substituted by ═O; and anyavailable nitrogen atoms in the ring are substituted by H,—C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(a)C(═O)C₁₋₆alkyl, —C(═O)R^(C)or —C₁₋₃alkylR^(c).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is a 9- or 10-membered bicyclic ring, containing1, 2, 3 or 4 N atoms with the remainder being carbon atoms, wherein eachof the carbon atoms of the ring is substituted by H, C₁₋₉alkyl,C₁₋₄haloalkyl, halo, cyano, oxo, —OR^(a), —S(═O)_(n)C₁₋₆alkyl,—OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—OC₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a), —NR^(a)C₁₋₄haloalkyl,—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl,—C(═O)OC₁₋₆alkyl, —OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or—NR^(a)C(═O)C₁₋₆alkyl; and unsaturated carbon atoms may be additionallysubstituted by ═O; and any available nitrogen atoms in the ring aresubstituted by H, —C₁₋₆alkylOR^(a), —C₁₋₆alkyl, —C₁₋₆alkylNR^(a)R^(a),—C₁₋₃alkylC(═O)OR^(a), —C₁₋₃alkylC(═O)NR^(a)R^(a),—C₁₋₃alkylOC(═O)C₁₋₆alkyl, —C₁₋₃alkylNR^(a)C (═O)C₁₋₆alkyl, —C(═O)R^(c)or —C₁₋₃alkylR^(c).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is a 10-membered bicyclic ring, comprisingvicinally-fused six-membered aromatic rings, containing 1 or 2 N atomswith the remainder being carbon atoms, wherein each of the carbon atomsof the ring is substituted by H, C₁₋₉alkyl, C₁₋₄ haloalkyl, halo, cyano,—OR^(a), —S(═O)_(r)C₁₋₆alkyl, —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —OC₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a),—NR^(a)C₁₋₄haloalkyl, —NC₂₋₆alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR₁₋₆alkyl, —C(═O)OC₁₋₆alkyl, —OC(═O)C₁₋₆alkyl,—C(═O)NR^(a)C₁₋₆alkyl or —NR^(a)C(═O)C₁₋₆alkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is selected from 2-quinolinyl, 3-quinolinyl,4-quinolinyl, 5-quinolinyl, 7-quinolinyl, 8-quinolinyl, 1-isoquinolinyl,3-isoquinolinyl, 4-isoquinolinyl, 5-isoquinolinyl, 6-isoquinolinyl,7-isoquinolinyl, 8-isoquinolinyl, 2-quinazolinyl, 4-quinazolinyl,5-quinazolinyl, 7-quinazolinyl and 8-quinazolinyl, any of which aresubstituted by 1 or 2 substituents selected from C₁₋₃alkyl,C₁₋₃haloalkyl, halo, cyano, —OCH₃, —OH, —NH₂ and —NHCH₃.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is an 8-, 9-, 10- or 11-membered bicyclic ring,containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from Sand O with the remainder being carbon atoms, wherein at least one of thecarbon atoms of the ring is substituted by C₁₋₉alkyl, C₁₋₄haloalkyl,halo, cyano, oxo, —OR^(a), —S(═O)_(n)C₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a)—OC₁₋₆alkylC(═O)OR^(a),—NR^(a)R^(a), —NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or —NR^(a)C(═O)C₁₋₆alkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is quinolin-8-yl or quinolin-7-yl wherein each ofthe carbon atoms of the quinolinyl ring is substituted by H, C₁₋₉alkyl,C₁₋₄haloalkyl, halo, cyano, oxo, —OR^(a), —S(═O)_(n)C₁₋₆alkyl,—OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOa —OC₁₋₆alkylC(═O)OR^(a), —NR^(a)R^(a), —NR^(a)C₁₋₄haloalkyl,—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), —C(═O)C₁₋₆alkyl,—C(═O)OC₁₋₆alkyl, —OC(═O)C₁₋₆alkyl, —C(═O)NR^(a)C₁₋₆alkyl or—NR^(a)C(═O)C₁₋₆alkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁵ and R⁹ are each independently selected from H,C₁₋₄haloalkyl, halo, nitro, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a), —NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a),—CO₂(C₁₋₆alkyl), —C(═O)(C₁₋₆alkyl), —C(═O)NR^(a)R^(a),—NR^(a)C(═O)R^(a), —NR^(a)C(═O)NR^(a)R^(a), —NR^(a)CO₂(C₁₋₆alkyl),—C₁₋₈alkylOR^(a), —C₁₋₆ alkylNR^(a)R^(a), —S(═O)_(n)(C₁₋₆alkyl),—S(═O)₂NR^(a)R^(a), —NR^(a)S(═O)₂(C₁₋₆alkyl) and —OC(═O)NR^(a)R^(a).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁵ and R⁹ are both H.

In another embodiment, in conjunction with any one of the above andbelow embodiments, at least one of R⁵ and R⁹ are selected fromC₁₋₄haloalkyl, halo, nitro, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a), —NR^(a)Cl₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C ₂₋₆alkylOR^(a),—CO₂(C₆alkyl), —C(═O)(C₁₋₆alkyl), —C(═O)NR^(a)R^(a), —NR^(a)C(═O)R^(a),—NR^(a)C(═O)NR^(a)R^(a), —NR^(a)CO₂(C₁₋₆alkyl), —C₁₋₈alkylOR^(a),C₂₋₆alkylNR^(a)R^(a), —S(═O)_(n)(C₁₋₆alkyl), —S(═O)₂NR^(a)R^(a),—NR^(a)S(═O)₂(C₁₋₆alkyl) and —OC(═O)NR^(a)R^(a).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁶ and R⁸ are each independently selected from H,C₁₋₅alkyl, C₁₋₄haloalkyl, halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a) or—NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a), —C₁₋₆ alkylNR^(a)R^(a) and—S(C₁₋₆alkyl).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁶ and R⁸ are both H.

In another embodiment, in conjunction with any one of the above andbelow embodiments, at least one of R⁶ and R⁸ is selected from C₁₋₅alkyl,C₁₋₄haloalkyl, halo, —OC₁₋₆alkyl, —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a) or —NR^(a)C₂₋₆alkylOR^(a), —C₁₋₉alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a) and —S(C₁₋₆alkyl).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁷ is independently, at each instance, C₁₋₈alkyl,C₁₋₄haloalkyl, —OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(a), —NR^(a)R^(a),—NR^(a)Cl₄ haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a) or—S(C₁₋₆alkyl).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁷ is C₁₋₅alkyl or C₁₋₃haloalkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹⁰ and R¹⁴ are each independently selected from H,C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl),—N(R^(a))C(═O)O(C₁₋₈alkyl)-N(R^(a))C(═O)NR^(a)R^(a),N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂(C₁₋₈alkyl),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and—NR^(a)C₂₋₆alkylOR^(a) and C₁₋₄alkyl substituted by 0, 1, 2 or 3 groupsselected from C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)(C₁₋₈alkyl),—C(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹¹ and R¹³ are independently, at each instance,selected from H, C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro,—C(═O)(C₁₋₈alkyl), —C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),NR^(a)R^(a), —N(R^(a))C(═O)O(C₁₋₈alkyl), —N(R^(a))C(═O)NR^(a)R^(a),N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂(C₁₋₈alkyl),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a) and C₁₋₄alkyl substituted by 0, 1, 2 or 3 groupsselected from C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹² is independently, at each instance, selected fromH, C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)O(C₁₋₈alkyl),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)(C₁₋₈alkyl),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR, —SR^(a), —S(═O)(C₁₋₈alkyl),—S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)O(C₁₋₅alkyl), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)(C₁₋₈alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹² isC₁₋₄alkyl substituted by 0, 1, 2 or 3 groups selected fromC₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)(C₁₋₈alkyl),—C(═O)O(C₁₋₈alkyl), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)(C₁₋₈alkyl), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂(C₁₋₈alkyl), —OC₂₋₆alkylNR^(a)R, —OC₂₋₆alkylOR,—SR^(a), —S(═O)(C₁₋₈alkyl), —S(═O)₂(C₁₋₈alkyl), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)(C₁₋₈alkyl), —S(═O)₂N(R^(a))C(═O)O(C₁₋₈alkyl),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)(C₈₋₁alkyl), —N(R^(a))C(═O)O(C₁₋₈alkyl),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂(C₁₋₈alkyl), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any one of the above andbelow embodiments, X is N and Y is C(R³).

In another embodiment, in conjunction with any one of the above andbelow embodiments, X is C(R²) and Y is N.

In another embodiment, in conjunction with any one of the above andbelow embodiments, X is C(R²) and Y is C(R³).

In another embodiment, in conjunction with any one of the above andbelow embodiments, J is O.

In another embodiment, in conjunction with any one of the above andbelow embodiments, J is S.

Another aspect of the invention relates to a method of treating acute,inflammatory and neuropathic pain, dental pain, general headache,migraine, cluster headache, mixed-vascular and non-vascular syndromes,tension headache, general inflammation, arthritis, rheumatic diseases,osteoarthritis, inflammatory bowel disorders, inflammatory eyedisorders, inflammatory or unstable bladder disorders, psoriasis, skincomplaints with inflammatory components, chronic inflammatoryconditions, inflammatory pain and associated hyperalgesia and allodynia,neuropathic pain and associated hyperalgesia and allodynia, diabeticneuropathy pain, causalgia, sympathetically maintained pain,deafferentation syndromes, asthma, epithelial tissue damage ordysfunction, herpes simplex, disturbances of visceral motility atrespiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritus, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders, comprising the step of administering a compound according toany of the above embodiments.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a compound according to any of the above embodiments and apharmaceutically-acceptable diluent or carrier.

Another aspect of the invention relates to the use of a compoundaccording to any of the above embodiments as a medicament.

Another aspect of the invention relates to the use of a compoundaccording to any of the above embodiments in the manufacture of amedicament for the treatment of acute, inflammatory and neuropathicpain, dental pain, general headache, migraine, cluster headache,mixed-vascular and non-vascular syndromes, tension headache, generalinflammation, arthritis, rheumatic diseases, osteoarthritis,inflammatory bowel disorders, inflammatory eye disorders, inflammatoryor unstable bladder disorders, psoriasis, skin complaints withinflammatory components, chronic inflammatory conditions, inflammatorypain and associated hyperalgesia and allodynia, neuropathic pain andassociated hyperalgesia and allodynia, diabetic neuropathy pain,causalgia, sympathetically maintained pain, deafferentation syndromes,asthma, epithelial tissue damage or dysfunction, herpes simplex,disturbances of visceral motility at respiratory, genitourinary,gastrointestinal or vascular regions, wounds, burns, allergic skinreactions, pruritus, vitiligo, general gastrointestinal disorders,gastric ulceration, duodenal ulcers, diarrhea, gastric lesions inducedby necrotising agents, hair growth, vasomotor or allergic rhinitis,bronchial disorders or bladder disorders.

Another aspect of the invention relates to a method of making a compoundaccording to the above embodiments, comprising the step of: reacting

with R⁴JH to form

The compounds of this invention may have in general several asymmetriccenters and are typically depicted in the form of racemic mixtures. Thisinvention is intended to encompass racemic mixtures, partially racemicmixtures and separate enantiomers and diasteromers.

Unless otherwise specified, the following definitions apply to termsfound in the specification and claims: “C_(α-β)alkyl” means an alkylgroup comprising a minimum of α and a maximum of β carbon atoms in abranched, cyclical or linear relationship or any combination of thethree, wherein α and β represent integers. The alkyl groups described inthis section may also contain one or two double or triple bonds.Examples of C₁₋₆alkyl include, but are not limited to the following:

“Benzo group”, alone or in combination, means the divalent radicalC₄H₄═, one representation of which is —CH═CH—CH═CH—, that when vicinallyattached to another ring forms a benzene-like ring—for exampletetrahydronaphthylene, indole and the like.The terms “oxo” and “thioxo” represent the groups ═O (as in carbonyl)and ═S (as in thiocarbonyl), respectively.“Halo” or “halogen” means a halogen atoms selected from F, Cl, Br and I.“C_(v-w)haloalkyl” means an alkyl group, as described above, wherein anynumber—at least one—of the hydrogen atoms attached to the alkyl chainare replaced by F, Cl, Br or I.“Heterocycle” means a ring comprising at least one carbon atom and atleast one other atom selected from N, O and S. Examples of heterocyclesthat may be found in the claims include, but are not limited to, thefollowing:

“Available nitrogen atoms” are those nitrogen atoms that are part of aheterocycle and are joined by two single bonds (e.g. piperidine),leaving an external bond available for substitution by, for example, Hor CH₃.“Pharmaceutically-acceptable salt” means a salt prepared by conventionalmeans, and are well known by those skilled in the art. The“pharmacologically acceptable salts” include basic salts of inorganicand organic acids, including but not limited to hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid,ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaricacid, citric acid, lactic acid, fumaric acid, succinic acid, maleicacid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid andthe like. When compounds of the invention include an acidic functionsuch as a carboxy group, then suitable pharmaceutically acceptablecation pairs for the carboxy group are well known to those skilled inthe art and include alkaline, alkaline earth, ammonium, quaternaryammonium cations and the like. For additional examples of“pharmacologically acceptable salts,” see infra and Berge et al., J.Pharm. Sci. 66:1 (1977).“Saturated or unsaturated” includes substituents saturated withhydrogens, substituents completely unsaturated with hydrogens andsubstituents partially saturated with hydrogens.“Leaving group” generally refers to groups readily displaceable by anucleophile, such as an amine, a thiol or an alcohol nucleophile. Suchleaving groups are well known in the art. Examples of such leavinggroups include, but are not limited to, N-hydroxysuccinimide,N-hydroxybenzotriazole, halides, triflates, tosylates and the like.Preferred leaving groups are indicated herein where appropriate.“Protecting group” generally refers to groups well known in the artwhich are used to prevent selected reactive groups, such as carboxy,amino, hydroxy, mercapto and the like, from undergoing undesiredreactions, such as nucleophilic, electrophilic, oxidation, reduction andthe like. Preferred protecting groups are indicated herein whereappropriate. Examples of amino protecting groups include, but are notlimited to, aralkyl, substituted aralkyl, cycloalkenylalkyl andsubstituted cycloalkenyl alkyl, allyl, substituted allyl, acyl,alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples ofaralkyl include, but are not limited to, benzyl, ortho-methylbenzyl,trityl and benzhydryl, which can be optionally substituted with halogen,alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts,such as phosphonium and ammonium salts. Examples of aryl groups includephenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl),phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl orsubstituted cycloalkylenylalkyl radicals, preferably have 6-10 carbonatoms, include, but are not limited to, cyclohexenyl methyl and thelike. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups includebenzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl,substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloro acetyl,phthaloyl and the like. A mixture of protecting groups can be used toprotect the same amino group, such as a primary amino group can beprotected by both an aralkyl group and an aralkoxycarbonyl group. Aminoprotecting groups can also form a heterocyclic ring with the nitrogen towhich they are attached, for example, 1,2-bis(methylene)benzene,phthalimidyl, succinimidyl, maleimidyl and the like and where theseheterocyclic groups can further include adjoining aryl and cycloalkylrings. In addition, the heterocyclic groups can be mono-, di- ortri-substituted, such as nitrophthalimidyl. Amino groups may also beprotected against undesired reactions, such as oxidation, through theformation of an addition salt, such as hydrochloride, toluenesulfonicacid, trifluoroacetic acid and the like. Many of the amino protectinggroups are also suitable for protecting carboxy, hydroxy and mercaptogroups. For example, aralkyl groups. Alkyl groups are also suitablegroups for protecting hydroxy and mercapto groups, such as tert-butyl.

Silyl protecting groups are silicon atoms optionally substituted by oneor more alkyl, aryl and aralkyl groups. Suitable silyl protecting groupsinclude, but are not limited to, trimethylsilyl, triethylsilyl,triisopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl,1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane anddiphenylmethylsilyl. Silylation of an amino groups provide mono- ordi-silylamino groups. Silylation of aminoalcohol compounds can lead to aN,N,O-trisilyl derivative. Removal of the silyl function from a silylether function is readily accomplished by treatment with, for example, ametal hydroxide or ammonium fluoride reagent, either as a discretereaction step or in situ during a reaction with the alcohol group.Suitable silylating agents are, for example, trimethylsilyl chloride,tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride,diphenylmethyl silyl chloride or their combination products withimidazole or DMF. Methods for silylation of amines and removal of silylprotecting groups are well known to those skilled in the art. Methods ofpreparation of these amine derivatives from corresponding amino acids,amino acid amides or amino acid esters are also well known to thoseskilled in the art of organic chemistry including amino acid/amino acidester or aminoalcohol chemistry.

Protecting groups are removed under conditions which will not affect theremaining portion of the molecule. These methods are well known in theart and include acid hydrolysis, hydrogenolysis and the like. Apreferred method involves removal of a protecting group, such as removalof a benzyloxycarbonyl group by hydrogenolysis utilizing palladium oncarbon in a suitable solvent system such as an alcohol, acetic acid, andthe like or mixtures thereof. A t-butoxycarbonyl protecting group can beremoved utilizing an inorganic or organic acid, such as HCl ortrifluoroacetic acid, in a suitable solvent system, such as dioxane ormethylene chloride. The resulting amino salt can readily be neutralizedto yield the free amine. Carboxy protecting group, such as methyl,ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can beremoved under hydrolysis and hydrogenolysis conditions well known tothose skilled in the art.

It should be noted that compounds of the invention may contain groupsthat may exist in tautomeric forms, such as cyclic and acyclic amidineand guanidine groups, heteroatom substituted heteroaryl groups (Y′═O, S,NR), and the like, which are illustrated in the following examples:

and though one form is named, described, displayed and/or claimedherein, all the tautomeric forms are intended to be inherently includedin such name, description, display and/or claim.

Prodrugs of the compounds of this invention are also contemplated bythis invention. A prodrug is an active or inactive compound that ismodified chemically through in vivo physiological action, such ashydrolysis, metabolism and the like, into a compound of this inventionfollowing administration of the prodrug to a patient. The suitabilityand techniques involved in making and using prodrugs are well known bythose skilled in the art. For a general discussion of prodrugs involvingesters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) andBundgaard Design of Prodrugs, Elsevier (1985). Examples of a maskedcarboxylate anion include a variety of esters, such as alkyl (forexample, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl(for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (forexample, pivaloyloxymethyl). Amines have been masked asarylcarbonyloxymethyl substituted derivatives which are cleaved byesterases in vivo releasing the free drug and formaldehyde (Bungaard J.Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, suchas imidazole, imide, indole and the like, have been masked withN-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)).Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloanand Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acidprodrugs, their preparation and use.

The specification and claims contain listing of species using thelanguage “selected from . . . and . . . ” and “is . . . or . . . ”(sometimes referred to as Markush groups). When this language is used inthis application, unless otherwise stated it is meant to include thegroup as a whole, or any single members thereof, or any subgroupsthereof. The use of this language is merely for shorthand purposes andis not meant in any way to limit the removal of individual elements orsubgroups as needed.

Experimental

General

Unless otherwise noted, all materials were obtained from commercialsuppliers and used without further purification. All parts are by weightand temperatures are in degrees centigrade unless otherwise indicated.All compounds showed NMR spectra consistent with their assignedstructures. Melting points were determined on a Buchi apparatus and areuncorrected. Mass spectral data was determined by electrosprayionization technique. All examples were purified to ≧95% purity asdetermined by high-performance liquid chromatography. Unless otherwisestated, reactions were run at room temperature under a nitrogenatmosphere. Microwave reactions were conducted using a SmithSynthesizer® (Personal Chemistry, Inc., Upssala, Sweden) apparatus.

The following abbreviations are used:

-   aq.—aqueous-   BINAP—2,2′-bis(diphenylphosphino)-1,1′-binaphthyl-   cond—concentrated-   DMF—N,N-dimethylformamide-   DMSO—methyl sulfoxide-   Et₂O—diethyl ether-   EtOAc—ethyl acetate-   EtOH—ethyl alcohol-   h—hour-   min—minutes-   MeOH—methyl alcohol-   satd—saturated-   THF—tetrahydrofuran    Generic Schemes for the Preparation of Pyridine Core (I):

Generic Schemes for the Preparation of Pyrimidine Core (II):

Generic Schemes for the Preparation of Pyridazine Core (III):

EXAMPLE 1

(a) 4-(4-tert-Butyl-phenyl)-6-chloro-pyrimidine. To a 250-mL,round-bottomed flask containing 4,6-dichloropyrimidine (4.0 g, 27 mmol,Aldrich) in CH₃CN (80 mL), was added 4-tert-butylphenylboronic acid (1.9g, 11 mmol, Aldrich) and Pd(PPh₃)₄ (0.62 g, 0.54 mmol, Aldrich). Asolution of 10% Na₂CO₃ (50 mL) was added, and the mixture was stirredunder N₂ at 90° C. for 8 h. The reaction mixture was allowed to cool toroom temperature and then EtOAc (200 mL) and 5% brine (80 mL) wereadded. A solid formed and was collected by filtration. The filtrate waspoured into a separatory funnel, and the organic layer was collected.The solid that had been previously collected and the organic phase werecombined and the resulting solution was concentrated in vacuum. Theresidue was dissolved in CH₂Cl₂, dried over Na₂SO₄, filtered, andconcentrated in vacuum. Silica gel chromatography with hexanes/EtOAc(5:1) gave the title compound as a white solid. MS (ESI, pos. ion.) m/z:247 (M+1).

(b) 4-(4-tert-Butyl-phenyl)-6-(3-methoxy-phenoxy)-pyrimidine. To a25-mL, round-bottomed flask containing4-(4-tert-butyl-phenyl)-6-chloro-pyrimidine (Example 1a) (0.10 g, 0.41mmol), 3-methoxyphenol (0.10 g, 0.81 mmol, Aldrich), and DMF (4 mL) atroom temperature was added NaH (0.032 g, 0.81 mmol, 60% disp. in oil).The reaction mixture turned green, and gas evolution was observed. Thesolution was stirred for 20 h under a N₂ atmosphere. The reaction wasquenched with H₂O (50 mL), and the solution was extracted with EtOAc(3×25 mL). The combined extracts were washed with H₂O (3×25 mL) andbrine, dried over Na₂SO₄, and adsorbed onto silica gel. The crudematerial was purified by chromatography (0 to 20% ethyl acetate/hexanes)on silica gel to afford the title compound as a white solid. Mp: 73-76°C. MS (ESI, pos. ion.) m/z: 335.1 (M+1).

EXAMPLE 2

(a) 4-Chloro-6-[4-(trifluoromethyl)phenyl]pyrimidine. To a 500-mL,round-bottomed flask was added 4,6-dichloropyrimidine (14 g, 95 mmol,Aldrich), 4-(trifluoromethyl)phenylboronic acid (6.0 g, 32 mmol,Aldrich), acetonitrile (95 mL), and 1 M sodium carbonate (95 mL). Themixture was sparged with N₂ for 15 min. Pd(PPh₃)₄ (1.9 g, 1.6 mmol,Strem) was then added, and the resulting yellow mixture was heated undera N₂ atmosphere at 80° C. for 15 h. After cooling to 25° C., thesolution was concentrated in vacuum, and the solution was diluted withaq. NaHCO₃ and extracted with CH₂Cl₂. The combined organic extracts weredried over Na₂SO₄, filtered and concentrated in vacuum. Purification bysilica gel chromatography (gradient, 1.5 to 10% ethyl acetate/hexanes)afforded the title compound as a white solid. MS (ESI, pos. ion) m/z:259 (M+1).

(b)8-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinolin-2-ylamine.To a 50-mL, round-bottomed flask was added NaH (175 mg, 4.37 mmol, 60%dispersion in mineral oil, Aldrich) and anhydrous DMF (10 mL). Theresulting suspension was stirred under N₂ at 25° C. and treated with2-amino-8-quinolinol (700 mg, 4.37 mmol, Sigma). After stirring for 10min at 25° C., the bright-yellow solution was treated with4-chloro-6-[4-(trifluoromethyl)phenyl]pyrimidine (1.24 g, 4.79 mmol) andstirred in a 50° C. oil bath for 3 h. The reaction mixture was allowedto cool to 25° C., diluted with 1 N NaOH (100 mL), and extracted withEtOAc (200 mL). The organic phase was washed with 1 N NaOH (100 mL),water (50 mL), satd NaCl (50 mL), dried over Na₂SO₄, filtered, andconcentrated in vacuum. Purification by silica gel chromatography (98:2dichloromethane: 2 M NH₃ in MeOH) afforded the title compound as a whitesolid. MP 203°0 C. MS (ESI, pos. ion) m/z: 383 (M+1).

EXAMPLE 2

(a) 2-Chloro-quinolin-8-ol. A mixture of 2,8-dihydroxyquinoline (4.0 g,25 mmol, Fluka) in POCl₃ (20 mL, Aldrich) was stirred at 100° C. for 1h. The mixture was allowed to cool to room temperature, and poured intoa mixture of ice (200 g) and 30% aq. NH₃ (100 mL). A white solid formedthat was collected by filtration and washed with water. The white solidwas dissolved in 12 N HCl (200 mL), and the resulting mixture wasstirred at 100° C for 1 h. The mixture was allowed to cool to roomtemperature and 30% aq. NH₃ was added until no further precipitationoccurred. The resulting white precipitate was collected by filtrationand dried in vacuum (25° C., 18 h) to yield the title compound. MS (ESI,pos. ion) m/z: 179.9 (M+1).

(b) 2-Azido-quinolin-8-ol. A mixture of 2-chloro-quinolin-8-ol (2.5 g,14 mmol) and sodium azide (4.6 g, 70 mmol, Aldrich) in DMF (20 mL) wasstirred at 110° C. for 16 h. After cooling to room temperature, water(50 mL) was added and the mixture was extracted with EtOAc (2×50 mL).The combined organic phases were washed with water (2×20 mL), brine (20mL), dried (Na₂SO₄), and filtered. After removing ca. ¾ of the solventin vacuum, a solid was formed. The solid was collected by filtration,washed with 20% EtOAc/hexanes and dried under house vacuum (25° C., 16h) to give the title compound. MS (ESI, pos. ion) m/z: 187.2 (M+1).

(c)2-Azido-8-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinoline. Amixture of 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example2(a), Method A), (2.0 g, 7.7 mmol), 2-chloro-quinolin-8-ol (3.0 g, 7.0mmol), and K₂CO₃ (1.9 g, 14 mmol) in DMF (15 mL) was stirred at 800C for6 h. After cooling to room temperature, water (50 mL) was added and themixture was extracted with EtOAc (2×100 mL). The combined organic phaseswere washed with water (2×30 mL), brine (30 mL), dried (Na₂SO₄), andfiltered. After removing ca. ¾ of the solvent in vacuum, a solid formedthat was collected by filtration. The solid was washed with 20%EtOAc/hexanes and dried under house vacuum (25° C., 16 h) to give thetitle compound. MS (ESI, pos. ion) m/z: 409.0 (M+1).

(d)8-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinolin-2-ylamine. Amixture of2-azido-8-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinoline(2.7 g, 6.6 mmol) and triphenylphosphine (3.5 g, 13 mmol, Aldrich) intoluene (50 mL) was heated at reflux for 4 h. The solvent was removed invacuum, and the residue was dissolved in AcOH:H₂O (2:1, 30 mL), and theresulting mixture was stirred at 50° C. for 18 h. After removing thesolvent in vacuum, the residue was purified by silica gel chromatographywith 60% EtOAc/hexanes. Following recrystalization from 20% ofEtOAc/hexanes the title compound was isolated. M.p. 225.6-227.9° C. MS(ESI, pos. ion) m/z: 382.8 (M+1); Anal. Calcd for C₂₀H₁₃F₃N₄O: C, 62.83;H, 3.43; N, 14.65; found: C, 62.53; H, 3.43; N, 14.74.

EXAMPLE 3

2-Chloro-8-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinoline.To a solution of 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine,(Example 2(a), Method A), (259 mg, 1 mmol) and 2-chloro-quinolin-8-ol(Example 2(a), Method B), (180 mg, 1 mmol) in 2 mL of DMF was addedpotassium carbonate (276 mg, 2 mmol). The reaction was stirred in a 90°C. oil bath for 2 h. EtOAc and brine were added, and the aqueous layerwas extracted with EtOAc. The combined EtOAc layers were washed withbrine, dried over Na₂SO₄, filtered, and concentrated in vacuum.Purification by flash chromatography by silica gel chromatography 1:4 ofEtOAc/hexanes as eluent gave the title compound as a white solid. MS(ESI, pos. ion) m/z: 402 (M+1). Mp: 171.5-173.0° C. Anal. Calcd forC₂₀H₁₁ClF₃N₃O: C, 59.79; H, 2.76; N, 10.46. Found: C, 60.01; H, 2.80; N,10.50.

EXAMPLE 4

4-(4-tert-Butyl-phenyl)-6-(3-methoxy-phenylsulfanyl)-pyrimidine. To a25-mL, round-bottomed flask containing4-(4-tert-butyl-phenyl)-6-chloro-pyrimidine, (Example 1(a)), (0.20 g,0.82 mmol), 3-methoxybenzenethiol (0.23 g, 1.6 mmol, Aldrich) and DMF (4mL) under a N₂ atmosphere at room temperature was added NaH (0.066 g,1.6 mmol, 60% disp. in oil, Aldrich). The mixture turned green and gasevolution was observed. The solution was stirred for 20 h at roomtemperature under a N₂ atmosphere. The reaction was quenched with H₂O(50 mL), and the resulting solution was extracted with EtOAc (3×25 mL).The combined extracts were washed with H₂O (3×25 mL) and brine, driedover Na₂SO₄, and adsorbed onto silica. The crude material was purifiedby chromatography (0 to 15% ethyl acetate/hexanes) on silica gel toafford the title compound as a colorless oil. MS (ESI, pos. ion.) m/z:351.2 (M+1).

EXAMPLE 5

(a) 2-Morpholin-4-yl-quinolin-8-ol. In a 5-mL vial was added2-chloro-quinolin-8-ol, (Example 2(a), Method B), (180 mg, 1 mmol),morpholine (1.75 mL, 20 mL), and 3 mL of dioxane. The reaction mixtrurewas heated in a microwave synthesizer at 220C for 12 min. The mixturewas partitioned between 1 N NaOH and EtOAc. The aqueous layer wasseparated and extracted with EtOAc, and the combined EtOAc layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated.Recrystallization from MeOH/H₂O provided the title compound as a tansolid. MS (ESI, pos. ion) m/z: 231 (M+1).

(b)2-Morpholin-4-yl-8-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinoline.This material was prepared according to the method described in Example3 using 2-chloro-4-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a),Method A), (196 mg, 0.76 mmol), 2-morpholin-4-yl-quinolin-8-ol (175 mg,0.76 mmol), and potassium carbonate (210 mg, 1.5 mmol) in DMF (1.5 mL).Purification by silica gel column chromatography (3:1 hexanes: EtOAc)provided the title compound as a white solid. MS (ESI, pos. ion) m/z:453 (M+1). Mp: 162.8-174.3° C. Anal. Calcd for C₂₄H₁₉F₃N₄O₂: C, 63.71;H, 4.23; N, 12.38. Found: C, 63.52; H, 4.24; N, 12.41.

EXAMPLE 6

7-[6-(4-tert-Butyl-phenyl)-pyrimidin-4-yloxy]-quinoline. To a 100-mL,round-bottomed flask containing4-(4-tert-butyl-phenyl)-6-chloro-pyrimidine, (Example 1(a)), (0.15 g,0.61 mmol) and 7-hydroxyquinoline (0.12 g, 0.85 mmol, Acros) in DMF (4mL), was added NaH (34 mg, 0.85 mmol, 60% in mineral oil, Aldrich) atroom temperature. The solution was then stirred at room temperature for4 h.After the solvent was removed in vacuum, the residue was taken up inEtOAc (10 mL), and the organic layers were washed with water (8 mL),dried over Na₂SO₄, filtered, and concentrated in vacuum. Silica gelchromatography (3:1 hexanes/EtOAc) gave the title compound as a whitesolid. Mp: 133-135° C. MS (ESI, pos. ion) m/z: 356 (M+1). Anal. Calcdfor C₂₃H₂₁N₃O: C, 77.72; H, 5.96; N, 11.82. Found: C, 77.43; H, 5.99; N,11.74.

EXAMPLE 7

2-Methoxy-8-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinoline.The title compound was prepared from4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine (Example 2(a), MethodA) and 2-methoxy-quinolin-8-ol (prepared according to Ataev, A; et al.Teoreticheskaya i Eksperimental'naya Khimya 1980, 16 (2), 243-249) underthe conditions of Example 6. Mp: 158.5-161° C. MS (ESI, pos. ion) m/z:398 (M+1).

EXAMPLE 8

8-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-isoquinoline. Thetitle compound was prepared from4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine (Example 2(a), MethodA) and isoquinolin-8-ol (MonomerChem) under the conditions of Example 6.Mp: 194-195° C. MS (ESI, pos. ion) m/z: 368.2 (M+1).

EXAMPLE 9

5-[6-(4-tert-Butyl-phenyl)-pyrimidin-4-yloxy]-1H-indole. To a 100-mL,round-bottomed flask containing4-(4-tert-butyl-phenyl)-6-chloro-pyrimidine, (Example l(a)), (0.15 g,0.61 mmol) and 5-hydroxyindole (0.24 g, 1.8 mmol, Aldrich) in1,4-dioxane (12 mL), was added NaOH (8.0 mL, 8.0 mmol, 1.0 N). Themixture was heated at reflux for 4 h, and after cooling to roomtemperature, the solvent was removed in vacuum. EtOAc (15 mL) was addedto the residue, and the organic layer was washed with 1 N NaOH (10 mL),water (10 mL), dried over Na₂SO₄, filtered, and concentrated in vacuum.After purifying the crude product by silica gel chromatography (4:1hexanes/EtOAc), the resulting solid was dissolved in acetone (3 mL).Water (5 mL) was added dropwise to this mixture, and a white precipitatefell out of solution, which was collected by filtration, washed withwater (0.5 mL), and dried under vacuum at 50° C. for 48 h to furnish thetitle compound. Mp: 143-145° C. MS (ESI, pos. ion) m/z: 344 (M+1). Anal.Calcd for C₂₂H₂₁N₃O·(H₂O)_(1/8): C, 76.44; H, 6.20; N, 12.16. Found: C,76.63; H, 6.20; N, 12.12.

EXAMPLE 10

5-[6-(4-tert-Butyl-phenyl)-pyrimidin-4-yloxy]-2-methyl-benzothiazole. Toa 100-mL, round-bottomed flask containing4-(4-tert-butyl-phenyl)-6-chloro-pyrimidine, (Example 1(a)), (0.15 g,0.61 mmol) and 2-methyl-benzothiazol-5-ol (0.14 g, 0.85 mmol, Aldrich)in DMF (10 mL), was added NaH (34 mg, 0.85 mmol, 60% in mineral oil,Aldrich) at room temperature. The solution was then stirred at roomtemperature for 4 h. After the solvent was removed in vacuum, EtOAc (10mL) was added to the residue, and the organic layer was washed withwater (8 mL), dried over Na₂SO₄, filtered, and concentrated in vacuum.After purifying the crude product by silica gel chromatography (4:1hexanes/EtOAc), the resulting solid was dissolved in acetone (5 mL).Water (8 mL) was added dropwise to this mixture, and a white precipitatefell out of solution, which was collected by filtration, washed withwater (0.5 mL), and dried under vacuum at 50° C. for 48 h to furnish thetitle compound. Mp: 163-165° C. MS (ESI, pos. ion) m/z: 376 (M+1). Anal.Calcd for C₂₃H₂₁N₃OS·(H₂O)_(1/3): C, 69.26; H, 5.72; N, 11.01. Found: C,69.19; H, 5.61; N, 11.03.

EXAMPLE 11

7-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinoline. To a250-mL, round-bottomed flask containing4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), MethodA), (2.5 g, 9.7 mmol) and 7-hydroxyquinoline (2.0 g, 14 mmol, Acros) inDMF (30 mL), was added NaH (5.4 g, 14 mmol, 60% in mineral oil, Aldrich)at room temperature The solution was then stirred at room temperaturefor 4 h. After the solvent was removed in vacuum, EtOAc (100 mL) andwater (50 mL) were added to the residue. The solid precipitate wasfiltered and the filtrate was poured into a separatory funnel. Theorganic layer was separated, combined with the previously isolatedsolid, concentrated in vacuum, and purified by silica gel chromatography(2:1 hexanes/EtOAc). The purified product was dissolved in acetone (30mL) and MeOH (10 mL), and to the solution was added water (30 mL) insmall portions. The precipitated solid was filtered, washed with water(5 mL), and dried under vacuum at 50° C. for 48 h to furnish the titlecompound as a white solid. Mp: 178-180° C. MS (ESI, pos. ion) m/z: 368(M+1). Anal. Calcd for C₂₀H₁₂F₃N₃O: C, 65.40; H, 3.29; N, 11.44. Found:C, 65.42; H, 3.23; N, 11.43.

EXAMPLE 12

4-(3-Methoxy-phenoxy)-6-(4-trifluoromethyl-phenyl)-pyrimidine. To a 100-mL, round-bottomed flask containing4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), MethodA), (0.15 g, 0.58 mmol) and 3-methoxyphenol (0.10 g, 0.81 mmol, Aldrich)in DMF (6 mL), was added NaH (32 mg, 0.81 mmol, 60% in mineral oil,Aldrich) at room temperature The solution was then stirred at roomtemperature for 4 h. After the solvent was removed in vacuum, EtOAc (10mL) was added to the residue, and the mixture was washed with water (8mL), dried over Na₂SO₄, filtered, and concentrated in vacuum. Silica gelchromatography (5:1 hexanes/EtOAc) afforded the title compound as awhite solid. Mp: 87-88° C. MS (ESI, pos. ion) m/z: 347 (M+1). Anal.Calcd for C₁₈H₁₃F₃N₂O₂: C, 62.54; H, 3.75; N, 8.09. Found: C, 62.54; H,3.75; N, 7.99.

EXAMPLE 13

(a) 1-Phenyl-2-(4-trifluoromethyl-phenyl)-ethanone. In a 250-mL,round-bottomed flask were added 1-bromo-4-trifluoromethyl-benzene (10 g,44 mmol, Aldrich), and THF (50 mL). Potassium bis(trimethylsilyl)amide(176 mL, 88.0 mmol, Aldrich), bis(dibenzylidene)acetone palladium (3.08g, 3.37 mmol, Acros) and 1,1′-bis(diphenylphosphino)ferrocene (2.2 g,3.99 mmol, Aldrich) were added to the reaction mixture. After stirringunder nitrogen for 10 min, acetophenone (5.4 mL, 46.6 mmol, Aldrich) wasadded, and the mixture was heated at reflux for 18 h. The reactionmixture was allowed to cool to room temperature, diluted with EtOAc (100mL) and washed with 0.5 M phosphoric acid (50 mL), H₂O (50 mL) and brine(50 mL). The organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuum. The crude material was purified by flash silicagel chromatography (5% EtOAc in hexanes) to give the title compound as adark brown oil. MS (ESI, pos.ion) m/z: 265 (M+1).

(b) 4-Oxo-4-phenyl-3-(4-trifluoromethyl-phenyl)-butyric acid ethylester. In a round-bottomed flask was placed sodium hydride (416 mg, 10.4mmol, 60% suspension in mineral oil, Aldrich) and washed twice withhexanes. Then 1-phenyl-2-(4-trifluromethyl-phenyl)ethanone (2.0 g, 7.57mmol) and DMSO (90 mL) were added and the reaction mixture was stirredfor 1 h at room temperature. Ethyl chloroacetate (1.05 mL, 10.4 mmol,Aldrich) was then added dropwise and the mixture was stirred at roomtemperature for 18 h. The reaction mixture was diluted with EtOAc (100mL) and the organic layer was washed with 0.5 M phosphoric acid (50 mL),H₂O (50 mL) and brine (50 mL). The organic layer was dried over Na₂SO₄,filtered and concentrated in vacuum to give the crude title compound asa tan oil. MS (ESI, pos.ion) m/z: 351 (M+1).

(c)6-Phenyl-5-(4-trifluoromethyl-phenyl)-4,5-dihydro-2H-pyridazin-3-one.Into a round-bottomed flask was placed4-oxo-4-phenyl-3-(4-trifluoromethyl-phenyl)-butyric acid ethyl ester(2.0 g, 5.71 mmol), dioxane (5 mL), and hydrazine (0.28 mL, 8.57 mmol,Aldrich), and the reaction mixture was heated at reflux for 18 h. Thereaction mixture was then diluted with EtOAc (100 mL) and the organiclayer was washed with 0.5 M phosphoric acid (50 mL), H₂O (50 mL) andbrine (50 mL). The organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuum to give the crude title compound as a tan oil. MS(ESI, pos.ion) m/z: 319 (M+1).

(d) 6-Phenyl-5-(4-trifluoromethyl-phenyl)-pyridazin-3-ol. Bromine (1.00g, 6.28 mmol) was added to a solution of6-phenyl-5-(4-trifluoromethyl-phenyl)-4,5-dihydro-2H-pyridazin-3-one(1.00 g, 3.14 mmol) in acetic acid (6 mL) and the mixture was heated at60C for 10 min. The reaction mixture was allowed to cool to roomtemperature, diluted with EtOAc (100 mL), washed with satd NaHCO₃ (100mL) and brine (50 mL), dried over Na₂SO₄, filtered, and concentrated invacuum to give the title compound. MS (ESI, pos.ion) m/z: 317 (M+1).

(e) 6-Chloro-3-phenyl-4-(4-trifluoromethyl-phenyl)-pyridazine. A mixtureof 6-phenyl-5-(4-trifluoromethyl-phenyl)-pyridazin-3-ol (1.00 g, 3.16mmol) and POCl₃ (6 mL) was heated at 100° C. for 18 h. After cooling thereaction to room temperature, the volatiles were removed in vacuum andthe residue was dissolved in EtOAc (100 mL). The solution was washedwith satd NaHCO₃ (100 mL) and brine (50 mL), dried over Na₂SO₄,filtered, and concentrated in vacuum. The crude product was purified byflash silica gel chromatography (10% EtOAc in hexanes) to give the titlecompound as a brown oil. MS (ESI, pos.ion) m/z: 335 (M+1).

(f)2-Azido-8-[6-phenyl-5-(4-trifluoromethyl-phenyl)-pyridazin-3-yloxy]-quinoline.Sodium hydride (19.6 mg, 0.816 mmol, 60% suspension in mineral oil,Aldrich) was added to a round-bottomed flask and washed twice withhexanes. 6-Chloro-3-phenyl-4-(4-trifluromethyl-phenyl)-pyridazine (250mg, 0.749 mmol) was then added, followed by 2-azido-quinolin-8-ol,(Example 2(b)), (123 mg, 0.680 mmol) and DMF (15 mL), and the mixturewas heated at 200° C. for 48 h. After cooling to room temperature, thereaction mixture was diluted with EtOAc, washed with H₂O and brine,dried over Na₂SO₄, filtered, and concentrated in vacuum to give thecrude title compound as a brown oil. MS (ESI, pos.ion) m/z: 485 (M+1).

(g)8-[6-Phenyl-5-(4-trifluoromethyl-phenyl)-pyridazin-3-yloxy]-quinolin-2-ylamine.A mixture of2-azido-8-[6-phenyl-5-(4-trifluoromethyl-phenyl)-pyridazin-3-yloxy]-quinoline(230 mg, 0.475 mmol), triphenylphosphine (249 mg, 0.950 mmol, Aldrich)and toluene (25 mL) was heated at reflux for 4 h. The solvent wasremoved in vacuum, the residue was treated with acetic acid and H₂O (10mL:5 mL) and the mixture was stirred at 50° C. for 18 h. The solvent wasremoved in vacuum and the residue was purified by silica gelchromatography (2.5% MeOH in dichloromethane) to afford the titlecompound as a white solid. MS (ESI, pos.ion) m/z: 459 (M+1). Mp:103-105° C.

EXAMPLE 14

8-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinoline. To a100-mL round-bottomed flask containing4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), MethodA), (0.30 g, 1.2 mmol) and 8-hydroxyquinoline (0.17 g, 1.2 mmol,Aldrich) in DMF (5 mL), was added NaH (56 mg, 1.4 mmol, 60% in mineraloil, Aldrich) at room temperature and the mixture was then stirred atroom temperature for 48 h. After the solvent was removed in vacuum,EtOAc (25 mL) was added to the residue, and the mixture was washed withwater (2×15 mL), dried over Na₂SO₄, filtered, and concentrated invacuum. Silica gel chromatography (4:1 hexanes/EtOAc) afforded the titlecompound as a white solid. Mp: 155-157° C. MS (ESI, pos. ion) m/z: 368(M+1). Anal. Calcd for C₂₀H₁₂F₃N₃O: C, 65.40; H, 3.29; N, 11.44. Found:C, 65.29; H, 3.25; N, 11.41.

EXAMPLE 15

6-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-1H-indole. To a100-mL, round-bottomed flask containing4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), MethodA), (0.20 g, 0.77 mmol) and 6-hydroxyindole (0.21 g, 1.5 mmol, Aldrich)in 1,4-dioxane (10 mL), was added NaOH (8.0 mL, 8.0 mmol, 1.0 N). Themixture was heated at reflux for 8 h, and after cooling to roomtemperature, the reaction mixture was concentrated in vacuum. EtOAc (30mL) was added, and the organic layer was washed with brine (10 mL),water (15 mL), dried over Na₂SO₄, filtered, and concentrated in vacuum.After the product was purified by silica gel chromatography (5:1hexanes/EtOAc), the residue was dissolved in acetone (3 mL). Water (4mL) was then added dropwise to afford a white precipitate, which wascollected by filtration, washed with water (0.5 mL), and dried undervacuum at 50° C. for 48 h to furnish the title compound. Mp: 206-209° C.MS (ESI, pos. ion) m/z: 356 (M+1); Anal. Calcd forC₁₉H₁₂F₃N₃O·(H₂O)_(0.2): C, 63.58; H, 3.48; N, 11.71. Found: C, 63.82;H, 3.37; N, 11.61

EXAMPLE 16

6-Methoxy-2-methyl-4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinoline.To a 100-mL, round bottomed flask containing4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), MethodA), (0.26 g, 1.0 mmol) and 6-methoxy-2-methyl-quinolin-4-ol (0.19 g, 1.0mmol, Ubichem) in DMF (5 mL), was added NaH (48 mg, 1.2 mmol, 60% inmineral oil, Aldrich) at room temperature The solution was then stirredat room temperature for 24 h. After the solvent was removed in vacuum,EtOAc (30 mL) was added to the residue, and the mixture was washed withbrine (2×15 mL), dried over Na₂SO₄, filtered, and concentrated invacuum. After the product was purified by silica gel chromatography (5:1hexanes/EtOAc), the resulting solid was dissolved in acetone (10 mL) andMeOH (8 mL). Water (15 mL) was then added dropwise to afford a whiteprecipitate, which was collected by filtration, washed with water (2mL), and dried under vacuum at 50° C. for 48 h to furnish the titlecompound. Mp: 165-166° C. MS (ESI, pos. ion) m/z: 412; Anal. Calcd forC₂₂H₁₆F₃N₃O₂: C, 64.23; H, 3.92; N, 10.21. Found: C, 64.20; H, 3.85; N,10.14.

EXAMPLE 17

(a) 4-(4-tert-Butyl-phenyl)-6-chloro-pyrimidin-2-ylamine. To a 250-mL,round-bottomed flask was added 2-amino-4,6-dichloropyrimidine (1.4 g,8.1 mmol, Aldrich), 4-tert-butyl-phenylboronic acid (1.2 g, 6.7 mmol,Aldrich), acetonitrile (30 mL), and 1 M aq. sodium carbonate (25 mL).Pd(PPh₃)₄ (0.39 g, 0.34 mmol, Strem) was then added and the resultingyellow mixture was heated under a N₂ atmosphere at 90° C. for 15 h. Thereaction mixture was allowed to cool to 25° C. and diluted with EtOAc(100 mL). The organic layer was separated, washed with water (30 mL),dried over Na₂SO₄, filtered and concentrated in vacuum. Purification ofthe residue by silica gel chromatography (gradient, 4:1 hexanes:EtOAc)afforded the title compound as clear oil. MS (ESI, pos. ion) m/z: 263(M+1).

(b) 4-(4-tert-Butyl-phenyl)-6-(quinolin-7-yloxy)-pyrimidin-2-ylamine. Toa 50-mL, round-bottomed flask was added4-(4-tert-butyl-phenyl)-6-chloro-pyrimidin-2-ylamine (0.25 g, 0.96mmol), 7-hydroxyquinoline (70 mg, 0.48 mmol, Acros), K₂CO₃ (66 mg, 0.48mmol) and anhydrous DMF (10 mL). The resulting suspension was heated at100° C. for 3 h with stirring under N₂. The reaction mixture was allowedto cool to 25° C., diluted with 1 N NaOH (100 mL), and extracted withEtOAc (50 mL). The organic phase was washed with 1 N NaOH (10 mL), water(10 mL), satd NaCl (10 mL), dried over Na₂SO₄, filtered, andconcentrated in vacuum. Purification of the residue by silica gelchromatography (gradient, 1:1 hexanes:EtOAc) afforded the title compoundas a white solid. Mp: 154-157° C. MS (ESI, pos. ion) m/z: 371 (M+1).

EXAMPLE 18

(a) 7-Benzyloxyquinoline. To a 250-mL, round-bottomed flask containing asolution of 7-hydroxyquinoline (2.3 g, 16 mmol, Acros) in DMF (15 mL)was added NaH (0.75 g, 19 mmol, 60% in mineral oil, Aldrich) in smallportion with stirring at 0° C. After stirring at 0° C. for 15 min, asolution of benzylbromide (1.9 mL, 16 mmol, Aldrich) in THF (10 mL) wasadded dropwise over 15 min at 0° C. After the addition, the mixture wasstirred at 0° C. for 30 min and diluted with EtOAc (65 mL) and water (30mL). The organic phase was separated, washed with water (2×20 mL), driedover Na₂SO₄, filtered and concentrated in vacuum. Purification of theresidue by silica gel chromatography (gradient, 1:1 hexanes:EtOAc) gavethe title compound. MS (ESI, pos. ion) m/z: 236 (M+1).

(b) 7-Benzyloxyquinoline 1-oxide. To a 100-mL, round-bottomed flaskcontaining a mixture of 7-benzyloxyquinoline (0.70 g, 3.0 mmol) andMeReO₃ (74 mg, 0.30 mmol, Aldrich) in dichloroethane (15 mL) was addeddropwise H₂O₂ ₍15 mL, 0.15 mol, 35 wt. % solution in water, Aldrich)over 10 min with stirring at room temperature. The mixture was thenstirred at room temperature for 3 h, diluted with water (15 mL) andextracted with CH₂Cl₂ (2×30 mL). The combined organic extracts werewashed with water (2×20 mL), dried over Na₂SO₄, filtered andconcentrated in vacuum to give the title compound. MS (ESI, pos. ion)m/z: 252 (M+1).

(c) 2-Chloro-7-benzyloxy-quinoline. To a 100-mL, round-bottomed flaskwas added 7-benzyloxyquinolin 1-oxide (0.72 g, 2.9 mmol) and POCl₃ (4.0mL, 44 mmol, Aldrich) and the mixture was heated at reflux for 3 h underN₂. After cooling to room temperature, the solvent was removed in vacuumand the residue was dissolved in EtOAc (50 mL). The solution was washedwith 5% K₂CO₃ (2×20 mL) and water (2×20 mL), dried over Na₂SO₄,filtered, and concentrated in vacuum. Chromatography of the residue oversilica gel (gradient: 3:1 hexanes:EtOAc) gave the title compound. MS(ESI, pos. ion) m/z: 270 (M+1).

(d) 2-Azido-7-benzyloxy-2-quinoline. To a 100-mL, round-bottomed flaskwas added 2-chloro-7-benzyloxy-quinoline (0.35 g, 1.3 mmol), NaN₃ (0.34g, 5.2 mmol, Aldrich) and DMSO (10 mL). The mixture was heated at refluxat 110° C. for 2 h, allowed to cool to room temperature, diluted withwater (10 mL) and extracted with EtOAc (2×50 mL). The combined organicextracts were washed with water (15 mL), dried over Na₂SO₄, filtered,and concentrated in vacuum. Chromatography of the residue over silicagel (gradient: 3:1 hexanes:EtOAc) gave the title compound. MS (ESI, pos.ion) m/z: 277 (M+1).

(e) 2-Azido-quinolin-7-ol. To a 100-mL, round-bottomed flask containinga solution of 2-azido-7-benzyloxy-2-quinoline (0.32 g, 1.2 mmol) inCH₂Cl₂ (5 mL) was added dropwise a 1.0 M solution of BBr₃ indichloromethane (5.8 mL, 5.8 mmol, Aldrich) with stirring at −40° C.under N₂. The reaction mixture was then stirred for 10 h at roomtemperature and quenched with ice-water (10 mL) with stirring andcooling with an ice bath. Most of the organic solvent was removed invacuum and the acidity of the aq. residue was adjusted to pH 5 with 2 NNaOH. The precipitated product was extracted with Et₂O (3×40 mL) and thecombined organic extracts were washed with water (20 mL), dried overNa₂SO₄, filtered, and concentrated in vacuum to give the title compound.MS (ESI, pos. ion) m/z: 187 (M+1).

(f) 2-Azido-7-[6-(4-trifluromethyl-phenyl)-pyrimidin-4-yloxy]-quinoline.To a 50-mL, round-bottomed flask was added4-chloro-6-[4-(trifluoromethyl)phenyl]-pyrimidine, (Example 2(a), MethodA), (0.27 g, 1.0 mmol), 2-azido-quinolin-7-ol (0.13 g, 0.69 mmol), K₂CO₃(0.19 g, 1.6 mmol) and anhydrous DMF (15 mL). The resulting suspensionwas stirred at 90° C. for 3 h under N₂. The reaction mixture was allowedto cool to 25° C., diluted with EtOAc (100 mL) and washed with 5% brine(35 mL). The organic phase was dried over Na₂SO₄, filtered andconcentrated in vacuum. Purification of the residue by silica gelchromatography (gradient: 2:1 hexanes:EtOAc) afforded the titlecompound. MS (ESI, pos. ion) m/z: 409 (M+1).

(g)7-[6-(4-Trifluromethyl-phenyl)-pyrimidin-4-yloxy]-quinolin-2-ylamine. Toa 50-mL, round-bottomed flask was added2-azido-7-[6-(4-trifluromethyl-phenyl)-pyrimidin-4-yloxy]-quinoline(0.20 g, 0.49 mmol), PPh₃ (0.26 g, 0.98 mmol, Aldrich), and toluene (10mL). The mixture was heated at reflux for 4 h, allowed to cool to roomtemperature and the solvent was removed in vacuum. To the residue wasadded water (3 mL) and AcOH (6 mL), and the resulting mixture was heatedat 50° C. for 5 h. The solvents were removed in vacuum and the residuewas dissolved in EtOAc (50 mL), washed with 5% K₂CO₃ (25 mL), water (25mL), dried over Na₂SO₄, filtered, and concentrated in vacuum. Theresidue was suspended in 5:1 CH₂Cl₂:MeOH and the title compound wasisolated as a solid by filtration. Purification of the filtrate bysilica gel chromatography (gradient: 10:1 EtOAc:MeOH) gave additionalamounts of the product, which combined with the solid from aboveafforded the title compound. Mp: 257-259° C. MS (ESI, pos. ion) m/z: 383(M+1).

EXAMPLE 19

(a) 3,4-Diamino-phenol sodium salt. To a 200-mL, round-bottomed flaskcontaining a solution of 1,2-diamino-4-methoxy-benzene (0.50 g, 3.6mmol, Avocado) in CH₂Cl₂ (5 mL) was added dropwise a solution of BBr₃ inCH₂Cl₂ (15 mL, 15 mmol, 1.0 M, Aldrich) with stirring at −30° C. underN₂. The mixture was stirred at room temperature for 5 h and quenchedwith ice water (25 mL) by cooling with and ice bath. The mixture wasbasified to pH 9 with 1 N NaOH and extracted with water (2×8 mL). Thecombined aq. extracts containing the title compound were used directlyin the next reaction. A small portion of the aq. solution wasneutralized with 1 N NaOH to give an analytical sample of3,4-diamino-phenol. MS (ESI, pos. ion) m/z: 125 (M+1).

(b) 7-Hydroxy-1,4-quinoxaline. To a 100-mL, round-bottomed flask wasadded aq. solution of 3,4-diamino-phenol sodium salt from step (a) above(1.6 mmol, 8 mL) and glyoxal (0.70 mL, 4.8 mmol, 40 wt. % solution inwater, Aldrich). The mixture was stirred at room temperature for 2 h,acidified to pH 5 with 2 N HCl and extracted with EtOAc:THF (3×20 mL,1:1). The combined organic extracts were washed with 5% brine (20 mL),dried over Na₂SO₄, filtered, and concentrated in vacuum. Purification ofthe residue by silica gel chromatography (gradient: 2:1 hexanes:EtOAc)afforded the title compound. MS (ESI, pos. ion) m/z: 147 (M+1).

(c) 6-[6-(4-Trifluromethyl-phenyl)-pyrimidin-4-yloxy]-quinoxaline. To a50-mL, round-bottomed flask was added4-chloro-6-[4-(trifluoromethyl)phenyl]-pyrimidine, (Example 2(a), MethodA), (0.40 g, 1.6 mmol), 7-hydroxy-1,4-quinoxaline (0.19 g, 1.3 mmol),anhydrous DMF (10 mL), and NaH (78 mg, 1.9 mmol, 60% dispersion inmineral oil, Aldrich), and the resulting suspension was stirred at 90°C. for 10 h under N₂. The reaction mixture was allowed to cool to roomtemperature, diluted with EtOAc (50 mL), washed with 5% brine (2×20 mL),dried over Na₂SO₄, filtered, and concentrated in vacuum. Purification ofthe residue by silica gel chromatography (gradient: 3:1 hexanes:EtOAc)afforded the title compound. Mp: 168-170° C. MS (ESI, pos. ion) m/z: 369(M+1).

EXAMPLE 20

(a) 4-Hydroxy-7-methoxy-quinoline-3-carboxylic acid. To a 200-mL,round-bottomed flask containing4-hydroxy-7-methoxy-quinoline-3-carboxylic acid ethyl ester (2.6 g, 11mmol, Aldrich) was added 2 N NaOH (25 mL, 50 mmol) and the mixture washeated at reflux for 3 h. After cooling to room temperature, the mixturewas neutralized to pH 7 with 2 N HCl and the white precipitate wasfiltered and dried under vacuum at 60° C. for 3 days to afford the titlecompound. MS (ESI, pos. ion) m/z: 220 (M+1).

(b) 7-Methoxy-4-hydroxy-quinoline. To a 50-mL, round-bottomed flask wasadded 4-hydroxy-7-methoxy-quinoline-3-carboxylic acid (1.2 g, 5.5 mmol)and phenyl ether (15 mL). The mixture was heated at 200° C. withstirring under N₂ for 1 h. After cooling to room temperature, themixture was diluted with EtOAc (50 mL) and washed with 1 N NaOH (30 mL).The aqueous phase was separated, acidified to pH 5 with 2 N HCl andextracted with EtOAc (3×40 mL). The combined extracts were dried overNa₂SO₄, filtered, and concentrated in vacuum to yield the title compoundas yellow oil. MS (ESI, pos. ion) m/z: 176 (M+1).

(c) 7-Methoxy-4-chloro-quinoline. To a 100-mL, round-bottomed flask wasadded 7-methoxy-4-hydroxy-quinoline (0.43 g, 2.5 mmol) and POCl₃ (5.0mL, 55 mmol, Aldrich), and the mixture was heated at reflux for 2 hunder N₂. After cooling to room temperature, the solvent was removed invacuum and the residue dissolved in EtOAc (40 mL). The solution waswashed with 5% K₂CO₃ (2×20 mL) and water (2×20 mL), dried over Na₂SO₄,filtered, and concentrated in vacuum. Chromatography of the residue oversilica gel (gradient: 3:1 hexanes:EtOAc) gave the title compound MS(ESI, pos. ion) m/z: 194 (M+1).

(d) 7-Hydroxy-4-chloro-quinoline. To a 100-mL, round-bottomed flaskcontaining a solution of 7-methoxy-4-chloro-quinoline (0.17 g, 0.86mmol) in dichloroethane (5 mL) was added dropwise a 1.0 M solution ofBBr₃ in dichloromethane (6.9 mL, 6.9 mmol, Aldrich) with stirring at−70° C. under N₂. The reaction mixture was then stirred for 20 h at roomtemperature and quenched with ice-water (10 mL) with stirring andcooling with an ice bath. Most of the organic solvent was removed invacuum and the acidity of the aq. residue was adjusted to pH 6 with 1 NNaOH. The precipitated product was extracted with Et₂O (3×20 mL) and thecombined organic extracts were washed with 5% brine (2×10 mL), driedover Na₂SO₄, filtered, and concentrated in vacuum to give the titlecompound. MS (ESI, pos. ion) m/z: 180 (M+1).

(e)4-Chloro-7-[6-(4-trifluromethyl-phenyl)-pyrimidin-4-yloxy]-quinoline. Toa 150-mL, round-bottomed flask was added4-chloro-6-[4-(trifluoromethyl)phenyl]-pyrimidine, (Example 2(a), MethodA), (0.35 g, 1.4 mmol), 7-hydroxy-4-chloro-quinoline (0.12 g, 0.68mmol), anhydrous DMF (8 mL), and NaH (54 mg, 1.4 mmol, 60% dispersion inmineral oil, Aldrich). The resulting suspension was stirred at roomtemperature for 6 h and then diluted with EtOAc (80 mL). The solutionwas washed with 5% brine (2×20 mL), dried over Na₂SO₄, filtered, andconcentrated in vacuum. Purification of the residue by silica gelchromatography (gradient: 3:1 hexanes:EtOAc) afforded the titlecompound. Mp: 205-208° C. MS (ESI, pos. ion) m/z: 402 (M+1).

EXAMPLE 21

(a) 7-Benzyloxycarbonyloxy-2-chloro-quinoline. The title compound wasprepared from 7-hydroxyquinoline (Acros) and benzyl chloroformate(Aldrich) in three steps analogous to the conditions of Example 18 (a),(b) and (c). MS (ESI, pos. ion) m/z: 314 (M+1).

(b) 7-Hydroxy-2-chloro-quinoline. To a 100-mL, round-bottomed flask wasadded 7-benzyloxycarbonyloxy-2-chloro-quinoline (0.32 g, 1.0 mmol), NaN₃(0.26 mg, 4.0 mmol, Aldrich), and DMF (10 mL) and the mixture was heatedat 100° C. for 3 h with stirring under N₂. After cooling to roomtemperature, the mixture was diluted with EtOAc (50 mL) and acidified topH 4 with 1 N HCl. The organic phase was separated, washed with 5% brine(2×20 mL), dried over Na₂SO₄, filtered, and concentrated in vacuum.Chromatography of the residue over silica gel (gradient: 3:1hexanes:EtOAc) gave the title compound. MS (ESI, pos. ion) m/z: 180(M+1).

(c)2-Chloro-7-[6-(4-trifluromethyl-phenyl)-pyrimidin-4-yloxy]-quinoline. Toa 50-mL, round-bottomed flask was added4-chloro-6-[4-(trifluoromethyl)phenyl]-pyrimidine, (Example 2(a), MethodA), (0.27 g, 1.0 mmol), 7-hydroxy-2-chloro-quinoline (56 mg, 0.31 mmol),K₂CO₃ (42 mg, 0.30 mmol) and anhydrous DMF (6 mL). The resultingsuspension was stirred at 90° C. for 4 h under N₂. The reaction mixturewas allowed to cool to 25° C., diluted with EtOAc (50 mL), washed with5% brine (15 mL), dried over Na₂SO₄, filtered, and concentrated invacuum. Purification of the residue by silica gel chromatography(gradient: 6:1 hexanes:EtOAc) afforded the title compound. Mp: 171-173°C. MS (ESI, pos. ion) m/z: 402 (M+1).

EXAMPLE 22

(a)4-Trifluoromethyl-7-[6-(4-trifluromethyl-phenyl)-pyrimidin-4-yloxy]-1H-quinolin-2-one.To a 250-mL, round-bottomed flask was added4-chloro-6-[4-(trifluoromethyl)phenyl]-pyrimidine, (Example 2(a), MethodA), (1.07 g, 4.1 mmol), 2,7-dihydroxy-4-trifluoromethylquinoline (0.79g, 3.5 mmol, Aldrich), K₂CO₃ (0.67 g, 4.8 mmol) and anhydrous DMF (15mL). The resulting suspension was heated at 90° C. for 4 h with stirringunder N₂. The reaction mixture was allowed to cool to 25° C., dilutedwith EtOAc (50 mL) and the white precipitate was filtered to give thetitle compound. MS (ESI, pos. ion) m/z: 452 (M+1).

(b)2-Chloro-4-trifluoromethyl-7-[6-(4-trifluromethyl-phenyl)-pyrimidin-4-yloxy]-quinoline.To a 250-mL, round-bottomed flask containing a solution of4-trifluoromethyl-7-[6-(4-trifluromethyl-phenyl)-pyrimidin-4-yloxy]-1H-quinolin-2-one(1.1 g, 2.4 mmol) in toluene (20 mL) was added dropwise POCl₃ (1.8 mL,19 mmol, Aldrich) with stirring at 0° C. under N₂. The reaction mixturewas stirred at room temperature for 0.5 h and heated at reflux for 5 h.The solvent was removed in vacuum and the residue dissolved in EtOAc(200 mL). The solution was washed with 5% K₂CO₃ (2×40 mL) and water(2×40 mL), dried over Na₂SO₄, filtered, and concentrated in vacuum.Recrystalization of the residue from CH₂Cl₂:MeOH (10:1) gave the titlecompound. Mp: 192-194° C. MS (ESI, pos. ion) m/z: 470 (M+1).

EXAMPLE 23

4-Trifluoromethyl-7-[6-(4-trifluromethyl-phenyl)-pyrimidin-4-yloxy]-quinoline.To a 100-mL, round-bottomed flask containing a solution of2-chloro-4-trifluoromethyl-7-[6-(4-trifluromethyl-phenyl)-pyrimidin-4-yloxy]-quinoline,(Example 22(b)), (0.25 g, 0.53 mmol) in EtOAc (20 mL) was added Zn (0.87g, 13 mmol, Aldrich), AcOH (61 mg, 1.1 mmol), and water (40 mg, 1.1mmol). The mixture was heated at 70° C. with stirring for 2.5 h. Aftercooling to room temperature, 5% aq. Na₂CO₃ was added and the reactionmixture was extracted with EtOAc (30 mL). The organic phase was washedwith water (2×10 mL), dried over Na₂SO₄, filtered, and concentrated invacuum. Purification of the residue by silica gel chromatography(gradient: 3:1 hexanes:EtOAc) gave the title compound. Mp: 129-131° C.MS (ESI, pos. ion) m/z: 436 (M+1).

EXAMPLE 24

(a) 4-piperazin-1-yl-quinolin-7-ol sodium salt. To a 100-mL,round-bottomed flask containing a solution of7-methoxy-4-piperazin-quinoline (0.40 g, 1.7 mmol, Ubichem, Plc.) indichloroethane (15 mL) was added dropwise a 1.0 M solution of BBr₃ indichloromethane (8.2 mL, 8.2 mmol, Aldrich) at −70° C. with stirringunder N₂. The mixture was stirred at room temperature for 20 h and thenquenched with ice water (20 mL) by cooling with an ice bath. Most of theorganic solvents were removed under vacuum and the aq. residue wasbasified with 1 N NaOH to pH 9. The aqueous was washed with EtOAc (30mL) to give and aq. solution of the title compound, which was useddirectly in the next reaction. A small portion of the aq. solution wasneutralized with 1 N NaOH to give an analytical sample of4-piperazin-1-yl-quinolin-7-ol. MS (ESI, pos. ion) m/z: 230 (M+1).

(b) 4-(7-Hydroxy-quinolin-4-yl)-piperazine-1-carboxylic acid tert-butylester. To a 100-mL, round-bottomed flask containing the aq. solution of4-piperazin-1-yl-quinolin-7-ol sodium salt from step (a) above (0.31 g,1.36 mmol) was added di-tert-butyl dicarbonate (0.42 g, 1.9 mmol,Aldrich), K₂CO₃ (0.38 g, 2.72 mmol, Aldrich), water (15 mL), and THF (25mL). The mixture was stirred at room temperature for 1 h, acidified topH 6 with 2 N HCl and extracted with EtOAc (50 mL). The organic phasewas washed with water (20 mL), dried over Na₂SO₄, filtered, andconcentrated in vacuum. Purification of the residue by silica gelchromatography (gradient: 5:5:1 hexanes:EtOAc:MeOH) gave the titlecompound. MS (ESI, pos. ion) m/z: 330 (M+1).

(c)4-{7-[6-(4-Trifluromethyl-phenyl)-pyrimidin-4-yloxy]-quinolin-4-yloxy}-piperazin-1-carboxylicacid tert-butyl ester. To a 100-mL, round-bottomed flask was added4-chloro-6-[4-(trifluoromethyl)phenyl]-pyrimidine, (Example 2(a), MethodA), (0.40 g, 1.5 mmol),4-(7-hydroxy-quinolin-4-yl)-piperazine-1-carboxylic acid tert-butylester (0.34 g, 1.0 mmol), K₂CO₃ (0.28 g, 2.0 mmol) and anhydrous DMF (12mL). The mixture was heated at 90° C. with stirring under N₂ for 2 h.The reaction mixture was allowed to cool to 25° C., diluted with EtOAc(80 mL), washed with water (20 mL), dried over Na₂SO₄, filtered, andconcentrated in vacuum. Purification of the residue by silica gelchromatography (gradient: 2:1 hexanes:EtOAc) gave the title compound MS(ESI, pos. ion) m/z: 552 (M+1).

(d)4-piperazin-1-yl-7-[6-(4-trifluromethyl-phenyl)-pyrimidin-4-yloxy]-quinoline.To a 100-mL, round-bottomed flask containing4-{7-[6-(4-trifluromethyl-phenyl)-pyrimidin-4-yloxy]-quinolin-4-yloxy}-piperazin-1-carboxylicacid tert-butyl ester (0.41 g, 0.74 mmol) in CH₂Cl₂ (15 mL), was addedCF₃COOH (15 mL, 195 mmol, Aldrich). The mixture was stirred at roomtemperature for 0.5 h and the solvent was removed in vacuum. The residuewas dissolved in EtOAc (40 mL), washed with 5% K₂CO₃ (2×20 mL) and water(2×10 mL), dried over Na₂SO₄, filtered, and concentrated in vacuum togive the title compound. Mp: 143-145° C. MS (ESI, pos. ion) m/z: 452(M+1).

EXAMPLE 25

(a) 2-(Benzhydrylidene-amino)-benzothiazol-6-ol. To a 200-mL,round-bottomed flask containing a solution of2-amino-6-hydroxy-benzothiazol (1.0 g, 6.0 mmol, Astatech, Inc.) in THF(30 mL), was added benzophenone (1.1 g, 6.0 mmol, Aldrich). The mixturewas heated at reflux for 3 h, allowed to cool to room temperature andthe solvents were evaporated in vacuum to yield the title compound. MS(ESI, pos. ion) m/z: 333 (M+1).

(b)6-[6-(4-Trifluromethyl-phenyl)-pyrimldin-4-yloxy]-benzothiazol-2-ylamine.To a 100-mL, round-bottomed flask was added4-chloro-6-[4-(trifluoromethyl)phenyl]-pyrimidine, (Example 2(a), MethodA), (0.26 g, 1.0 mmol), 2-(benzhydrylidene-amino)-benzothiazol-6-ol(0.39 g, 1.2 mmol), K₂CO₃ (0.25 g, 1.8 mmol) and anhydrous DMF (10 mL).The resulting suspension was heated at 50° C. with stirring under N₂ for5 h. The reaction mixture was allowed to cool to 25° C., diluted withEtOAc (45 mL), washed with 5% brine (2×20 mL), dried over Na₂SO₄,filtered, and concentrated in vacuum. To the residue was added acetone(15 mL) and 1 N NaOH (15 mL), and the mixture was stirred at roomtemperature for 15 min. The mixture was extracted with EtOAc (40 mL) andthe organic phase was separated, washed with 5% brine (2×20 mL), driedover Na₂SO₄, filtered, and concentrated in vacuum. Purification of theresidue by silica gel chromatography (gradient: 20:10:3hexanes:Et-OAc:MeOH) gave the title compound. Mp: 222-225° C. MS (ESI,pos. ion) m/z: 389 (M+1).

EXAMPLE 26

2-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-phenylamine. To amixture of 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example2(a), Method A), (0.52 g, 2.0 mmol) and 2-aminophenol (0.26 g, 2.4 mmol,Aldrich) in DMF (10 mL) was added sodium hydride (0.09 g, 2.2 mmol, 60%dispersion in mineral oil, Aldrich). The mixture was heated at 50° C.for 2 h, allowed to cool to room temperature and diluted with H₂O. Theresulting solid was filtered, washed with H₂O and dried in vacuum atroom temperature for 20 h to afford the title compound as a whitepowder. Mp: 188° C., MS (ESI, pos. ion) m/z: 332 (M+1).

EXAMPLE 27

N-{2-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-phenyl}-butyramide.To a mixture of2-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-phenylamine, (Example26), (0.33 g, 1.0 mmol), butyryl chloride (0.15 mL, 1.5 mmol, Aldrich),and 4-dimethylaminopyridine (0.006 g, 0.05 mmol, Aldrich) in CH₂Cl₂ (5mL) was added Et₃N (0.21 mL, 1.5 mmol, Aldrich). The mixture was stirredfor 30 min, diluted with hexanes (10 ml) and treated with H₂O (2 mL).The resulting solids were filtered, washed with H₂O and hexanes, anddried in vacuum for 16 h at room temperature to give the title compoundas a white powder. Mp: 112° C., MS (ESI, pos. ion) m/z: 402 (M+1).

EXAMPLE 28

8-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-1H-quinolin-2-one. Toa mixture of 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example2(a), Method A), (0.10 g, 0.39 mmol) and 2,8-quinolinediol (0.075 g,0.46 mmol, Fluka) in acetonitrile (5 mL) was added1,8-diazabicyclo[5.4.0]undec-7-ene (0.069 mL, 0.46 mmol, Aldrich). Themixture was heated to reflux for 6 h, allowed to cool to roomtemperature, and diluted with EtOAc. The solids were filtered, washedwith EtOAc and dried in vacuum for 16 h to yield the title compound aslong white needles. Mp: 312° C., MS (ESI, pos. ion) m/z: 384 (M+1).

EXAMPLE 29

2-Methyl-8-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinoxaline.To a mixture of 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine,(Example 2(a), Method A), (0.20 g, 0.77 mmol) and3-methyl-quinoxalin-5-ol (0.14 g, 0.85 mmol, prepared according to J.Med. Chem. 1988, 41, 4062-4079.) in DMF (3 mL) was added sodium hydride(0.040 g, 1.0 mmol, 60% dispersion in mineral oil, Aldrich). Thereaction was heated at 60° C. for 24 h, allowed to cool to roomtemperature and partitioned between EtOAc and H₂O. The aqueous layer wasextracted with EtOAc (4 x). The combined organic layers were dried overMgSO₄, filtered and the solvent was removed in vacuum. The residue waspurified by flash chromatography (0→75% EtOAc/hexanes) to give the titlecompound as an ivory powder. Mp: 139-141° C., MS (ESI, pos. ion) m/z:383 (M+1).

EXAMPLE 30

2-Methyl-5-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinoxaline.The title compound was prepared analogous to the procedure in Example 29using 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a),Method A), (0.20 g, 0.77 mmol), 2-methyl-quinoxalin-5-ol (0.14 g, 0.85mmol, J. Med. Chem, 1988, 41, 4062.) DMF (3 mL), and a 60% dispersion ofsodium hydride in mineral oil (0.040 g, 1.0 mmol, Aldrich). Purificationby flash chromatography (0→75% EtOAc/hexanes) gave the title compound asan ivory powder. Mp: 135-141° C., MS (ESI, pos. ion) m/z: 383 (M+1).

EXAMPLE 31

(a) Quinoxalin-5-ol. To a suspension of 2,3-diaminophenol (1.5 g, 12mmol, Aldrich) in 2 M acetic acid (24 mL) and 4 M sodium acetate (15 mL)was added a solution of 40% aq. glyoxal (1.4 mL, 12.4 mmol, Aldrich).The mixture was heated at 60° C. for 40 min, allowed to cool to roomtemperature and the pH of the solution was adjusted to pH 8 with satdaq. NaHCO₃. The solution was extracted with CH₂Cl₂ (3×). The combinedorganic layers were washed with satd aq. NaHCO₃, H₂O, and brine. Theorgainic layer was dried over MgSO₄ and concentrated in vacuum.Purification by flash chromatography (0→20% EtOAc/hexanes) gave thetitle compound as a yellow powder. MS (ESI, pos. ion) m/z: 147 (M+1).

(b) 5-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinoxaline. Thetitle compound was prepared analogous to the procedure in Example 29using 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a),Method A), (0.30 g, 1.2 mmol), quinoxalin-5-ol (0.19 g, 1.3 mmol) DMF (5mL), and a 60% dispersion of sodium hydride in mineral oil (0.060 g, 1.5mmol, Aldrich). Purification by flash chromatography (0→75%EtOAc/hexanes) gave the title compound as a white powder. MS (ESI, pos.ion) m/z: 369 (M+1).

EXAMPLE 32

(a) 3-Methoxy-2-nitro-phenylamine. A mixture of 2-amino-3-nitrophenol(25.0 g, 162 mmol, Aldrich) and K₂CO₃ (27 g, 195 mmol) in DMF (65 ml)was stirred at room temperature for 1 h. Methyl iodide (12.2 mL, 195mmol, Aldrich) was added and the reaction was stirred at roomtemperature for 30 h. The reaction was diluted with H₂O and extractedwith EtOAc (3×). The combined organic layers were dried over Na₂SO₄,filtered and concentrated in vacuum. The dark-red solid wasrecrystallized from hexanes to yield the title compound as orangeneedles. MS (ESI, pos. ion) m/z: 169 (M+1).

(b) 3-Methoxy-benzene-1,2-diamine sulfate. A mixture of3-methoxy-2-nitro-phenylamine (4.6 g, 27 mmol), iron powder (10.7 g, 191mmol, Aldrich), EtOH (130 mL) and H₂O (10 mL) was heated at 50° C. Asolution of HCl (12.1 M, 1.7 mL) was added dropwise with stirring. Themixture was heated to reflux for 3 h and allowed to cool to roomtemperature. After neutralization with NaOH and filtration throughCeliteo®, the solvent was removed in vacuum and the residue waspartitioned between CH₂Cl₂ and satd aq. NaHCO₃. After extraction withCH₂Cl₂ (3×), the combined organic layers were concentrated. The residuewas re-dissolved in of EtOH (30 mL) and treated with concentrated H₂SO₄until no more precipitate was formed. The resulting solid was removed byfiltration, washed with EtOH and dried in vacuum for 20 h at roomtemperature giving the title compound as an off-white powder. MS (ESI,pos. ion) m/z: 139 (M−HSO₄ ⁻).

(c) 8-Methoxy-1H-quinoxalin-2-one and 5-Methoxy-1H-quinoxalin-2-one. Asolution of 3-methoxy-benzene-1,2-diamine sulfate (4.1 g, 17 mmol) inEtOH (21 mL) and H₂O (48 mL) was neutralized by careful addition ofsolid NaHCO₃. After addition of ethyl glyoxylate solution (50% intoluene, 3.8 mL, 19 mmol, Fluka) the mixture was heated to reflux for 1h. The reaction was allowed to cool and partitioned between satd aq.NH₄Cl and 25% i-PrOH/CHCl₃. The aqueous layer was extracted with 25%i-PrOH/CHCl₃ (3×). The combined organic layers were dried over Na₂SO₄,filtered and concentrated in vacuum. Purification by silica gelchromatography (0→2.5% MeOH/CH₂Cl₂) afforded8-methoxy-1H-quinoxalin-2-one as an off-white powder [MS (ESI, pos. ion)m/z: 177 (M+1)] and 5-methoxy-1H-quinoxalin-2-one as an off-white powder[MS (ESI, pos. ion) m/z: 177 (M+1)].

(d) 8-Hydroxy-1H-quinoxalin-2-one. To a suspension of8-methoxy-1H-quinoxalin-2-one (0.3 g, 1.7 mmol) in benzene (20 ml) wasadded AlCl₃ (2.0 g, 15.5 mmol, Aldrich) and the mixture was heated toreflux for 2 h. The reaction was allowed to cool to room temperature andquenched by careful addition of satd aq. NaHCO₃. The resulting mixturewas extracted with 25% i-PrOH/CHCl₃ (5×). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated in vacuum.Purification by flash chromatography (0→8% MeOH/CH₂Cl₂) afforded thetitle compound as a brown powder. MS (ESI, pos. ion) m/z: 163 (M+1).

(e)8-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-1H-quinoxalin-2-one.To a suspension of 8-hydroxy-1H-quinoxalin-2-one (0.22 g, 1.4 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL, 1.6 mmol, Aldrich) in CH₃CN(20 mL) was added 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine,(Example 2(a), Method A), (0.43 g, 1.6 mmol). The solution was heated toreflux for 18 h, allowed to cool to room temperature and concentrated invacuum. Purification by flash chromatography (0→80% EtOAc/hexanes)afforded the title compound as as an off-white powder. Mp:>265° C., MS(ESI, pos. ion) m/z: 385 (M+1).

EXAMPLE 33

8-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-3,4-dihydro-1H-quinoxalin-2-one.To a suspension of8-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-1H-quinoxalin-2-one,(Example 32(e)), (0.25 g, 0.65 mmol) in EtOH (5 mL) was added sodiumborohydride (0.11 mg, 2.8 mmol, Aldrich). After stirring at roomtemperature for 2 h, the mixture was quenched with satd aq. NaHCO₃ andextracted with 25% i-PrOH/CHCl₃ (3×). The combined organic layers weredried over Na₂SO₄, filtered and concentrated. Purification by flashchromatography (0→1.5% 2M NH₃/MeOH in CH₂Cl₂) gave the title compound asa light-yellow powder. Mp: 305° C., MS (ESI, pos. ion) m/z: 387 (M+1).

EXAMPLE 34

(a) 5-Hydroxy-1H-quinoxalin-2-one. The title compound was preparedanalogous to the method used in Example 32(d) using5-methoxy-1H-quinoxalin-2-one, (Example 32(c)), (0.3 g, 1.7 mmol) andAlCl₃ (2.0 g, 15.5 mmol, Aldrich) in benzene (20 mL). Purification byflash chromatography (0→8% MeOH/CH₂Cl₂) afforded the title compound as abrown powder. MS (ESI, pos. ion) m/z: 163 (M+1).

(b)5-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-1H-quinoxalin-2-one.The title compound was prepared analogous to the methods used in Example32(e) using 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example2(a), Method A), (0.38 g, 1.5 mmol), 5-hydroxy-1H-quinoxalin-2-one (0.20g, 1.2 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL, 1.5 mmol,Aldrich) in CH₃CN (20 mL). Purification by flash chromatography (0→80%EtOAc/hexanes) afforded the title compound as an off-white powder.Mp>265° C., MS (ESI, pos. ion) m/z: 385 (M+1).

EXAMPLE 35

5-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-3,4-dihydro-1H-quinoxalin-2-one.The title compound was prepared analogous to the methods used in Example33 using5-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-1H-quinoxalin-2-one,(Example 34(b)), (0.25 g, 0.65 mmol) and sodium borohydride (0.11 mg,2.8 mmol, Aldrich) in EtOH (5 mL). Purification by flash chromatography(0→1.5% 2M NH₃/MeOH in CH₂Cl₂) gave the title compound as a light-yellowpowder. Mp: 305° C., MS (ESI, pos. ion) m/z: 387 (M+1).

EXAMPLE 36

(a)2-Bromo-5-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinoxaline.A mixture of5-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-1H-quinoxalin-2-one,(Example 34(b)), (0.5 g, 1.3 mmol) and POBr₃ (10.0 g, 35 mmol,Alfa-Aesar) was heated at 105° C. for 2 h. The mixture was allowed tocool to room temperature, dissolved in CH₂Cl₂ and carefully treated withsatd aq. NaHCO₃. The aqueous layer was extracted with CH₂Cl₂ (4×). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated. Purification by flash chromatography (0→1.5% 2M NH₃/MeOHin CH₂Cl₂) gave the title compound as a white powder. Mp: 81° C., MS(ESI, pos. ion) m/z: 447 (M+1).

(b)2-Methoxy-5-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinoxaline.To a solution of2-bromo-5-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinoxaline(0.12 g, 0.27 mmol) in MeOH (5 mL) was added a solution of sodiummethoxide (25% in MeOH, 0.090 ml, 0.33 mmol, Aldrich). The solution wasstirred at room temperature for 24 h. Water was added and the productwas extracted with 25% i-PrOH/CHCl₃ (4×). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated in vacuum.Purification by flash chromatography (0→25% EtOAc/hexanes) gave thetitle compound as white crystals (0.088 g, 81%). Mp: 162° C., MS (ESI,pos. ion) m/z: 399 (M+1).

EXAMPLE 37

(a) 2-Chloro-8-methoxy-quinoxaline. A mixture of8-methoxy-1H-quinoxalin-2-one, (Example 32(c)), (0.62 g, 3.5 mmol, andPOCl₃ (6.0 mL, 64 mmol, Aldrich) was heated at 105° C. for 4 h. Thereaction was allowed to cool to room temperature and concentrated invacuum. The residue was partitioned between satd aq. NaHCO₃ and CH₂Cl₂and stirred for 3 h. The aqueous layer was extracted with CH₂Cl₂ (3×).The combined organic layers were dried over Na₂SO₄ and filtered throughsilica gel, eluting with EtOAc. The solvent was removed in vacuum. MS(ESI, pos. ion) m/z: 195 (M+1).

(b) 8-Methoxy-quinoxalin-2-ylamine. A mixture of2-chloro-8-methoxy-quinoxaline (0.42 g, 2.2 mmol) and CuI (0.21 g, 1.1mmol, Aldrich) in cond NH₄OH (1.5 mL, Baker) was heated at 140° C. in amicrowave synthesizer for 10 min. The reaction was diluted with H₂O andthe solids were removed by filtration, and washed with copious amountsof H₂O. The brown powder was dried in vacuum for 20 h at roomtemperature. MS (ESI, pos. ion) m/z: 176 (M+1).

(c) 3-Amino-quinoxalin-5-ol. The title compound was prepared analogousto the methods used in Example 32(d) using8-methoxy-quinoxalin-2-ylamine (0.12 g, 0.68 mmol) and AlCl₃ (0.82 g,6.2 mmol, Aldrich) in benzene (10 mL). Purification by flashchromatography (0→7.5% MeOH/CH₂Cl₂) afforded the title compound as abrown powder. MS (ESI, pos. ion) m/z: 162 (M+1).

(d)8-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinoxa-2-ylamine.The title compound was prepared analogous to the methods used in Example32(e) using 4-chloro-6-(4-trifluoromethyl-phenyl)-pyriridine, (Example2(a), Method A), (0.13 g, 0.51 mmol), 3-amino-quinoxalin-5-ol (0.069 g,0.43 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.077 mL, 0.51 mmol,Aldrich) in CH₃CN (5 mL). Purification by flash chromatography (0→75%EtOAc/hexanes) afforded the title compound as an off-white powder. Mp215° C., MS (ESI, pos. ion) m/z: 384 (M+1).

EXAMPLE 38

N-{8-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinoxalin-2-yl}-acetamide.A mixture of8-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinoxalin-2-ylamine,(Example 37(d)), (0.55 g, 1.4 mmol) and acetic anhydride (0.82 mL, 8.6mmol, Aldrich) in toluene (15 mL) was heated at 75° C. for 4 h.After stirring at room temperature for 16 h the mixture was treated withhexanes. The solids were removed by filtration, washed with hexanes anddried in vacuum for 24 h at room temperature to give the title compoundas a tan powder. Mp: 237° C., MS (ESI, pos. ion) m/z: 426 (M+1).

EXAMPLE 39

(a) 2-Chloro-5-methoxy-quinoxaline. The title compound was preparedanalogous to the methods in Example 37(a) from5-methoxy-1H-quinoxalin-2-one, (Example 32(c)), (0.47 g, 2.7 mmol) andPOCl₃ (6.0 mL, 64 mmol, Aldrich). MS (ESI, pos. ion) m/z: 195 (M+1).

(b) 5-Methoxy-quinoxalin-2-ylamine. The title compound was preparedanalogous to the method in Example 37(b) with2-chloro-5-methoxy-quinoxaline (0.2 g, 1.0 mmol) and CuI (0.098 g, 0.52mmol, Aldrich) in NH₄OH (1.5 mL, Baker) and 15 isolated as a tan powder.MS (ESI, pos. ion) m/z: 176 (M+1).

(c) 2-Amino-quinoxalin-5-ol. The title compound was prepared analogousto the methods used in Example 32(d) using5-methoxy-quinoxalin-2-ylamine (0.15 g, 0.88 mmol) and AlC₃ (1.1 g, 8.0mmol, Aldrich) in benzene (10 mL). Purification by flash chromatography(0→7.5% MeOH/CH₂Cl₂) afforded the title compound as a brown powder. MS(ESI, pos. ion) m/z: 162 (M+1).

(d)5-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinoxalin-2-ylamine.The title compound was prepared analogous to the methods used in Example32(e) using 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example2(a), Method A), (0.2 g, 0.85 mmol), 2-amino-quinoxalin-5-ol (0.11 g,0.71 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL, 0.85 mmol,Aldrich) in CH₃CN (10 mL). Purification by flash chromatography (0→75%EtOAc/hexanes) afforded the title compound as an off-white powder. Mp225° C., MS (ESI, pos. ion) m/z: 384 (M+1).

EXAMPLE 40

(a) 3-Amino-8-methoxy-1H-quinoxalin-2-one and3-Amino-5-methoxy-1H-quinoxalin-2-one. To a suspension of3-methoxy-benzene-1,2-diamine sulfate (Example 32(b)), (2.36 g, 10 mmol)in EtOH (15 mL) and H₂O (1 mL) was added NaHCO₃ (1.68 g, 20 mmol, J TBaker). When gas evolution was complete, ethoxy-imino-acetic acid ethylester (1.6 g, 11 mmol, prepared according to J. Chem. Soc. Perkin.Trans. 1, 1999, 1789.) was added and the mixture was stirred at roomtemperature for 16 h. The reaction was diluted with satd aq. NaHCO₃ andextracted with 25% i-PrOH/CHCl₃ (5×). The combined organic layers weredried over Na₂SO₄, filtered and concentrated in vacuum. Purification byflash chromatography (0→5% MeOH/CH₂Cl₂) afforded3-amino-8-methoxy-1H-quinoxalin-2-one as a light-brown powder [0.75 g,39%, MS (ESI, pos. ion) m/z: 192 (M+1)] and3-amino-5-methoxy-1H-quinoxalin-2-one as a light-brown powder [MS (ESI,pos. ion) m/z: 192 (M+1)].

(b) 3-Amino-8-hydroxy-1H-quinoxalin-2-one. The title compound wasprepared analogous to the methods used in Example 32(d) using3-amino-8-methoxy-1H-quinoxalin-2-one (0.75 g, 3.9 mmol) and AlCl₃ (4.7g, 35 mmol, Aldrich) in benzene (50 mL). The reaction was quenched bycareful addition of satd aq. NaHCO₃ and the solids were removed byfiltration through Celite®. The filter cake was washed with H₂O and DMSOto remove the product and the filtrate was concentrated in vacuum. TheDMSO was removed by azeotropic distillation with H₂O to give the titlecompound. MS (ESI, pos. ion) m/z: 178 (M+1).

(c)3-Amino-8-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-1H-quinoxalin-2-one.The title compound was prepared analogous to the methods used in Example32(e) using 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine (1.0 g, 3.9mmol), 3-amino-8-hydroxy-1H-quinoxalin-2-one (0.69 g, 3.9 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.70 mL, 4.7 mmol, Aldrich) in CH₃CN(50 mL). Purification by flash chromatography (0→2.5% MeOH/CH₂Cl₂)afforded the title compound as a white powder. Mp 288° C., MS (ESI, pos.ion) m/z: 400 (M+1).

EXAMPLE 41

7-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-1H-quinolin-2-one.The title compound was prepared analogous to the methods used in Example32(e) using 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example2(a), Method A), (0.50 g, 1.9 mmol), 7-hydroxy-1H-quinolin-2-one (0.37g, 2.3 mmol, prepared according to Synthesis 1997, 87-90) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 mL, 2.3 mmol, Aldrich) in CH₃CN(40 mL). Purification by flash chromatography (0→2.5% MeOH/CH₂Cl₂)afforded the title compound as an off-white powder. Mp 288° C. MS (ESI,pos. ion) m/z: 384 (M+1).

EXAMPLE 42

1-Methyl-8-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-1H-quinoxalin-2-one.To a mixture of8-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-1H-quinoxalin-2-one,(Example 32(e)), (0.10 g, 0.26 mmol) and K₂CO₃ (0.043 g, 0.31 mmol,Aldrich) in DMF (1 mL) was added iodomethane (0.019 mL, 0.31 mmol,Aldrich). The mixture was stirred at room temperature for 20 h, dilutedwith water and extracted with 25% i-PrOH/CHCl₃ (3×). After beingconcentrated in vacuum, the residue was purified by flash chromatography(0→2% 2M NH₃ in MeOH/CH₂Cl₂) to afford the title compound as anoff-white amorphous solid. Mp:158° C. MS (ESI, pos. ion) m/z: 399 (M+1).

EXAMPLE 43

1-Methyl-5-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-1H-quinoxalin-2-one.The title compound was prepared analogous to the methods used in Example42 using5-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-1H-quinoxalin-2-one,(Example 34(b)), (0.10 g, 0.26 mmol), K₂CO₃ (0.043 g, 0.31 mmol,Aldrich) and iodomethane (0.019 mL, 0.31 mmol, Aldrich) in DMF (1 mL).Purification by flash chromatography (0→5% 2M NH₃ in MeOH/CH₂Cl₂)afforded the title compound as a white amorphous solid. Mp: 258° C. MS(ESI, pos. ion) m/z: 399 (M+1)

EXAMPLE 44

(a) 3-Amino-5-hydroxy-1H-quinoxalin-2-one. The title compound wasprepared analogous to the methods used in Example 32(d) using3-amino-5-methoxy-1H-quinoxalin-2-one, (Example 40(a)), (0.47 g, 2.5mmol) and AlCl₃ (0.97 g, 7.4 mmol, Aldrich) in benzene (25 mL). Thereaction was quenched by careful addition of satd aq. NaHCO₃ andextracted with 25% i-PrOH/CHCl₃ (5×). The combined organic layers weredried over Na₂SO₄, filtered and concentrated in vacuum to afford thetitle compound as a brown powder. MS (ESI, pos. ion) m/z: 178 (M+1).

(b)3-Amino-5-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-1H-quinoxalin-2-one.A solution of 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example2(a), Method A), (0.49 g, 1.9 mmol),3-amino-5-hydroxy-1H-quinoxalin-2-one (0.33 g, 1.9 mmol) and K₂CO₃ (0.31g, 2.3 mmol, Aldrich) in DMSO (5 mL) was stirred at room temperature for64 h. The mixture was then heated at 100° C. for 2 h, allowed to cool toroom temperature, diluted with H₂O, and the solids were collected byfiltration. The solids were purified by flash silica gel chromatography(0→2.5% 2M.NH₃ in MeOH/CH₂Cl₂) to afford the title compound as anoff-white amorphous solid. Mp: 334° C., MS (ESI, pos. ion) m/z: 400(M+1).

EXAMPLE 45

(a) Potassium (Z)-3-(4-trifluoromethylphenyl)-3-cyanopropenoate.(Analogous to the procedure of Dan, W. D. and Blum, D. M. J. Org. Chem.1993, 58, 7916-7917). Glyoxylic acid monohydrate (111.86 g, 1.22 mol,Aldrich) was added portion wise to a suspension of potassium carbonate(284.4 g, 2.06 mol) in methanol (1.6 L) with stirring and cooling with awater bath. To the light-brown suspension was then added4-trifluoromethylphenylacetonitrile (150 g, 0.81 mol, Aldrich) in smallportions, the mixture was stirred for 5 h at room temperature, and theresulting thick solid precipitate was filtered and washed withdichloromethane. Concentration of the filtrate to a 600 mL volume led tothe precipitation of additional amount of solid, which was filtered andwashed with dichloromethane. The solids were combined and then suspendedin cold water (4 L) to remove the excess of potassium carbonate. Theprecipitate was filtered, washed with water and air-dried to provide thetitle compound as a white solid, which was used in the next step withoutadditional purification. MS (ESI, pos. ion) m/z: 279 (M).

(b) 4-Trifluoromethylphenylmaleic anhydride. (Analogous to the procedureof Dan, W. D. and Blum, D.M. J. Org. Chem. 1993, 58, 7916-7917).Potassium (Z)-3-(4-trifluoromethylphenyl)-3-cyanopropenoate (100 g, 358mmol) was dissolved in 88% formic acid (600 mL, Aldrich) containing condsulfuric acid (45 mL) and the mixture heated at reflux for 3 h. Thereaction mixture was then allowed to cool to room temperature and pouredinto ice water (1 L). The resulting solid was filtered, washed withwater and air dried to give the title compound as a pale-yellow solid,which was used in the next step without additional purification. MS(ESI, pos. ion) m/z: 243 (M+1).

(c) 4-(4-Trifluoromethylphenyl)-1,2-dihydropyridazine-3,6-dione.(Analogous to the procedure of Augustin, M. and Reinemann, P. Z. Chem.1973, 13, 12-13). 4-Trifluoromethylphenylmaleic anhydride (57.2 g, 235.8mmol) was added to a mixture of water (325 mL) and acetic acid (88 mL),followed by the dropwise addition of hydrazine hydrate (11.44 mL, 235.8mmol, Aldrich) with stirring at room temperature. To the resultingpale-yellow suspension was then added dropwise cond sulfuric acid (177mL) with stirring and cooling in an ice bath, which led to the formationof a thick paste. The reaction mixture was heated at 100-115° C. for 3 hwith stirring, and then cooled in an ice bath. The precipitate waswashed with water until the filtrate showed neutral pH, and then waswashed with diethyl ether (2×100 mL) and air-dried to give the titlecompound as a white solid, which was used in the next step withoutadditional purification. MS (ESI, pos. ion) m/z: 257 (M+1).

(d) 3,6-Dichloro-4-(4-trifluoromethylphenyl)pyridazine. (Analogous tothe procedure of Augustin, M. and Reinemann, P. Z. Chem. 1973, 13,12-13). A mixture of4-(4-trifluoromethylphenyl)-1,2-dihydropyridazine-3,6-dione (25.6 g, 100mmol) and phosphorus oxychloride (192 mL) was heated at reflux for 2 hwith stirring under nitrogen atmosphere. The reaction mixture wasallowed to cool to room temperature and poured in small portions withvigorous stirring into a mixture of water and crushed ice (2.6 L). Theproduct separated as a white precipitate, which was filtered, washedwith water (3×50 mL), dried under vacuum and recrystallized fromdioxane/methanol to give the title compound as a white solid. MS (ESI,pos. ion) m/z: 293 (M+1).

(e) 6-Chloro-3,4-bis-(4-trifluoromethyl-phenyl)-pyridazine. A flaskcontaining 3,6-dichloro-4-(4-trifluoromethyl-phenyl)-pyridazine (996 mg,3.4 mmol), 4-(trifluoromethyl)phenylboronic acid (647 mg, 3.4 mmol,Aldrich), Na₂CO₃ (1.81 g, 17 mmol, Mallinkrodt) andtetrakis(triphenylphosphine)palladium (0) (120 mg, 0.1 mmol, Strem) wasevacuated and purged with N₂ three times. To the flask was added DME (24mL) and H₂O (8 mL). The reaction was equipped with an argon balloon andheated at 90° C. for 20 h. The reaction was allowed to cool to roomtemperature and the solvent was removed in vacuum. The residue waspartitioned between H₂O/CH₂Cl₂ and the layers were separated. Theaqueous layer was extracted with CH₂Cl₂ and the combined organic layerswere evaporated onto SiO₂. Purification by silica gel chromatographywith EtOAc/hexanes (0:1→1:9) as eluant afforded the title compound as atan amorphous solid. MS (ESI, pos. ion) m/z: 403 (M+1).

(f)5-[5,6-Bis-(4-trifluoromethyl-phenyl)-pyridazin-3-yloxy]-2-methyl-benzothiazole.To a solution of 6-chloro-3,4-bis-(4-trifluoromethyl-phenyl)-pyridazine(177 mg, 0.4 mmol) and 2-methyl-5-benzothiazolol (72 mg, 0.4 mmol) inN,N-dimethylacetamide (5 mL) was added NaH (25 mg, 0.6 mmol, 60%suspension in mineral oil, Aldrich) and the mixture was stirred at roomtemperature for 6 h. The solvent was removed in vacuum and the residuewas partitioned between brine/EtOAc. The aqueous layer was separated andextracted with EtOAc. The combined organic layers were evaporated ontoSiO₂ and purified by flash silica gel chromatography with 2M NH₃ inMeOH/CH₂Cl₂ (0:1→3:197) as eluant. A second purification by silica gelchromatography with EtOAc/hexanes (0:1→1:4) as eluant gave the titlecompound as a pale yellow amorphous solid. Mp: 175-177° C. MS (ESI, posion.) m/z: 532 (M+1).

EXAMPLE 46

7-[6-Phenyl-5-(4-trifluoromethyl-phenyl)-pyridazin-3-yloxy]-quinoline.To a solution of6-chloro-3-phenyl-4-(4-trifluoromethyl-phenyl)-pyridazine, (Example 13(e)), (106 mg, 0.3 mmol) and 7-hydroxyquinoline (55 mg, 0.4 mmol, Acros)in DMF (2.5 mL) was added NaH (22 mg, 0.6 mmol, 60% suspension inmineral oil, Aldrich) and the mixture was stired at room temperature for15 h. The reaction mixture was then heated at 50° C. for another 28 h,allowed to cool to room temperature and the solvent removed in vacuum.The residue was partitioned between EtOAc/H₂O and the aqueous layer wasextracted with EtOAc. The combined organic layers were evaporated ontoSiO₂ and purified by flash silica gel chromatography with EtOAc/hexanes(0:1→3:7) as eluant to give the title 15 compound as an off-whiteamorphous solid. Mp: 178-183° C. MS (ESI, pos ion.) m/z: 444 (M+1).

EXAMPLE 47

2-Methyl-5-[6-phenyl-5-(4-trifluoromethyl-phenyl)-pyridazin-3-yloxy]-benzothiazole.The title compound was prepared analogous to the procedure used toprepare Example 45(f), using 2-methyl-5-benzothiazolol (117 mg, 0.7mmol, Aldrich),6-chloro-3-phenyl-4-(4-trifluoromethyl-phenyl)-pyridazine, (Example13(e)), (197 mg, 0.6 mmol) and NaH (37 mg, 0.9 mmol, 60% suspension inmineral oil, Aldrich) in DMF (5 mL). Purification by flash silica gelchromatography with 2 M NH₃ in MeOH/CH₂Cl₂ (0:1→1:49) as eluant gave thetitle compound as a pale-orange amorphous solid. Mp: 208-209° C. MS(ESI, pos ion.) m/z: 464 (M+1).

EXAMPLE 48

7-[(6-(7-Quinolinyloxy)-4-(4(trifluoromethyl)phenyl)-3-pyridazinyl)oxy]-quinoline.To a solution of 3,6-dichloro-4-(4-trifluoromethyl-phenyl)-pyridazine,(Example 45(d)), (441 mg, 1.5 mmol) and 7-hydroxyquinoline (441 mg, 3.0mmol, Acros) in DMF (10 mL) was added 60% NaH (150 mg, 3.8 mmol) and themixture was heated at 80C for 14 h. The solvent was removed in vacuum,the residue was partitioned between EtOAc/H₂O and the aqueous layer wasextracted with EtOAc. The combined organic layers were evaporated ontoSiO₂ and purified by flash silica gel chromatography with EtOAc/hexanes(0:1→1:0) as eluant to give the title compound as an off-white amorphoussolid. Mp: 158-162° C. MS (ESI, pos ion.) m/z: 511 (M+1).

EXAMPLE 49

7-[(7-Isoquinolinyloxy)-4-(4-(trifluoromethyl)phenyl)-3-pyridazinyl)oxy]-isoquinoline.The title compound was prepared analogous to the procedure used toprepare Example 48, using3,6-dichloro-4-(4-trifluoromethyl-phenyl)-pyridazine, (Example 45(d)),(443 mg, 1.5 mmol), 7-hydroxyisoquinoline (444 mg, 3.1 mmol, Lancaster)and NaH (151 mg, 3.8 mmol, 60% suspension in mineral oil, Aldrich) inDMF (10 mL). Purification by flash silica gel chromatography with 2M NH₃in MeOH/CH₂Cl₂ (0:1→1:24) as eluant gave the title compound as a tanamorphous solid. Mp: 82-86° C. MS (ESI, pos ion.) m/z: 511 (M+1).

EXAMPLE 50

5-((6-(5-Isoquinolinyloxy)-4-(4(trifluoromethyl)phenyl)-3-pyridazinyl)oxy)-isoquinoline.To a solution of 3,6-dichloro-4-(4-trifluoromethyl-phenyl)-pyridazine,(Example 45(d)), (100 mg, 0.3 mmol) and 5-hydroxyisoquinoline (112 mg,0.7 mmol, Aldrich) in DMF (2.5 mL) was added NaH (32 mg, 0.8 mmol, 60 %suspension in mineral oil, Aldrich) and the reaction mixture was heatedat 140° C. for 10 min in a microwave synthesizer. The reaction mixturewas allowed to cool to room temperature and partitioned betweenH₂O/CH₂Cl₂. The aqueous layer was extracted with CH₂Cl₂ and the combinedorganic layers were concentrated in vacuum. The residue was evaporatedonto SiO₂ and purified by flash silica gel chromatography with 2M NH3 inMeOH/CH₂Cl₂ (0:1→1:49) as eluant to give the title compound as an whiteamorphous solid. Mp: 197-199° C. MS (ESI, pos ion.) m/z: 511 (M+1).

EXAMPLE 51

(a) 3-Chloro-6-methoxy-4-(4-trifluoromethyl-phenyl)-pyridazine. To asolution of 3,6-dichloro-4-(4-trifluoromethyl-phenyl)-pyridazine,(Example 45(d)), (4.0 g, 14 mmol) in MeOH (50 mL) was added NaOH (607mg, 15 mmol) and the mixture was stirred at room temperature for 16 h.The solvent was removed in vacuum and the residue was partitionedbetween H₂O/CHCl₃. The aqueous layer was extracted with CHCl₃ and thecombined organic layers were evaporated onto SiO₂. Purification by flashsilica gel chromatography with EtOAc/hexanes (0:1→1:9) as eluant gavethe title compound as a white amorphous solid. MS (ESI, pos ion.) m/z:289 (M+1).

(b) 6-Methoxy-3-naphthalen-2-yl-4-(4-trifluoromethyl-phenyl)-pyridazine.A mixture of 3-chloro-6-methoxy-4-(4-trifluoromethyl-phenyl)-pyridazine(434 mg, 1.5 mmol), 2-napthaleneboronic acid (314 mg, 1.8 mmol,Aldrich), Na₂CO₃ (640 mg, 6.0 mmol, Mallinkrodt) andtetrakis(triphenylphosphine)palladium (0) (125 mg, 0.11 mmol, Strem) inH₂O (1 mL) and DME (3 mL) was heated at 140C for 30 min in a microwavesynthesizer. The reaction mixture was partitioned between H₂O/CH₂Cl₂ andthe aqueous layer was extracted with CH₂Cl₂. The combined organic layerswere evaporated onto SiO₂ and purified by flash silica gelchromatography with EtOAc/hexanes (0:1→1:9) as eluant to give the titlecompound as a colorless foam. MS (ESI, pos ion.) m/z: 381 (M+1).

(c) 6-Naphthalen-2-yl-5-(4-trifluoromethyl-phenyl)-pyridazin-3-ol. Amixture of6-methoxy-3-naphthalen-2-yl-4-(4-trifluoromethyl-phenyl)-pyridazine (389mg, 1.02 mmol) and 47% HI (3 mL) in MeOH (5 mL) was heated at 65° C. for1.5 h then at 75° C. for 6 h. The mixture was allowed to cool to roomtemperature and the resulting precipitate was filtered, washed with H₂Oand dried in vacuum to give the title compound as a white crystallinesolid. MS (ESI, pos ion.) m/z: 367 (M+1).

(d) 6-Chloro-3-naphthalen-2-yl-4-(4-trifluoromethyl-phenyl)-pyridazine.A flask charged with6-naphthalen-2-yl-5-(4-trifluoromethyl-phenyl)-pyridazin-3-ol (300 mg,0.8 mmol) and POCl₃ (5.0 mL, 54 mmol, Aldrich) was heated at 105° C. for3.5 h. The reaction was allowed to cool to room temperature and theexcess of POCl₃ was removed in vacuum. The residue was dissolved inCH₂Cl₂ and ice was added. The layers were separated and the aqueouslayer was extracted with CH₂Cl₂. The combined organic layers were washedwith diluted NaHCO₃, dried over Na₂SO₄, filtered and the solventevaporated in vacuum. Purification of the residue by silica gelchromatography with EtOAc/hexanes (0:1→1:2) afforded the title compound.MS (ESI, pos ion.) m/z: 385 (M+1).

(e)7-[6-Naphthalen-2-yl-5-(4-trifluoromethyl-phenyl)-pyridazin-3-yloxy]-quinoline.The title compound was prepared analogous to the procedure used toprepare Example 46, using6-chloro-3-naphthalen-2-yl-4-(4-trifluoromethyl-phenyl)-pyridazine (251mg, 0.7 mmol), 7-hydroxyquinoline (98 mg, 0.7 mmol, Acros) and NaH (37mg, 0.9 mmol, 60% suspension in mineral oil, Aldrich) in DMF (2.5 mL).Purification by flash silica gel chromatography with EtOAc/hexanes(0:1→1:2) as eluant gave the title compound as an white amorphous solid.Mp: 194-195° C. MS (ESI, pos ion.) m/z: 494 (M+1).

EXAMPLE 52

(a)3-(4-Fluoro-phenyl)-6-methoxy-4-(4-trifluoromethyl-phenyl)-pyridazine.The title compound was prepared analogous to the procedure used toprepare Example 51(b), using3-chloro-6-methoxy-4-(4-trifluoromethyl-phenyl)-pyridazine, (Example51(a)), (500 mg, 1.7 mmol), 4-fluorophenylboronic acid (287 mg, 2.1mmol, Aldrich), Na₂CO₃ (694 mg, 6.5 mmol, Mallinkrodt) andtetrakis(triphenylphosphine)palladium (0) (145 mg, 0.1 mmol, Strem) inH₂O (1.5 mL) and DME (3.5 mL), and heating at 150° C. for 25 min in amicrowave synthesizer. This procedure was run in duplicate. The reactionmixtures were combined, partitioned between EtOAc/H₂O and the aqueouslayer was extracted with EtOAc. The combined organic layers wereevaporated onto SiO₂ and purified by flash silica gel chromatographywith EtOAc/hexanes (0:1→3:17) as eluant to give the title compound as anoff-white amorphous solid. MS (ESI, pos ion.) m/z: 349 (M+1).

(b) 6-(4-Fluoro-phenyl)-5-(4-trifluoromethyl-phenyl)-pyridazin-3-ol. Thetitle compound was prepared analogous to the procedure used to prepareExample 51(c), using3-(4-fluoro-phenyl)-6-methoxy-4-(4-trifluoromethyl-phenyl)-pyridazine(384 mg, 1.1 mmol), 47% HI (3 mL) and MeOH (3 mL) and heating to 75° C.for 14 h afforded the title compound as a white amorphous solid. MS(ESI, pos ion.) m/z: 335 (M+1); MS (ESI, neg ion.) m/z: 333 (M−1).

(c)6-Chloro-3-(4-fluoro-phenyl)-4-(4-trifluoromethyl-phenyl)-pyridazine.The title compound was prepared analogous to the procedure used toprepare Example 51(d), using6-(4-fluoro-phenyl)-5-(4-trifluoromethyl-phenyl)-pyridazin-3-ol (300 mg,0.9 mmol) and POCl₃ (5.0 mL, 54 mmol, Aldrich). The crude material waspassed through a short pad of SiO₂ eluting with EtOAc to give the titlecompound as a light yellow oil. MS (ESI, pos ion.) m/z: 353 (M+1).

(d)7-[6-(4-Fluoro-phenyl)-5-(4-trifluoromethyl-phenyl)-pyridazin-3-yloxy]-quinoline.The title compound was prepared analogous to the procedure used toprepare Example 46, using6-chloro-3-(4-fluoro-phenyl)-4-(4-trifluoromethyl-phenyl)-pyridazine(315 mg, 0.9 mmol), 7-hydroxyquinoline (128 mg, 0.9 mmol, Acros) and NaH(50 mg, 1.25 mmol, 60% suspension in mineral oil, Aldrich) in DMF (2.5mL). Purification by flash silica gel chromatography with EtOAc/hexanes(0:1→1:1) as eluant gave the title compound as a white amorphous solid.Mp: 191-194° C. MS (ESI, pos ion.) m/z: 462 (M+1).

EXAMPLE 53

(a) 6-Chloro-5-(4-trifluoromethyl-phenyl)-pyridazin-3-ylamine and6-Chloro-4-(4-trifluoromethyl-phenyl)-pyridazin-3-ylamine. A mixture of3,6-dichloro-4-(4-trifluoromethyl-phenyl)-pyridazine, (Example 45(d)),28-30% aq. NH4OH (13 mL, Baker) and EtOH (1 mL) was heated at 130-140°C. with stirring in a sealed tube for 22 h. The reaction mixture wasallowed to cool to room temperature and the light precipitate wasfiltered, washed with water and dried in the air. The dried precipitatewas suspended in Et₂O and filtered to give 0.814 g (40%) of6-chloro-5-(4-trifluoromethyl-phenyl)-pyridazin-3-ylamine as pale-yellowneedles. MS (ESI, pos ion.) m/z: 274 (M+1). The filtrate was evaporatedin vacuum and the residue purified by flash SiO₂ chromatography withEtOAc/hexanes (1:1→1:0) as eluant to give the fast running6-chloro-4-(4-trifluoromethyl-phenyl)-pyridazin-3-ylamine as apale-yellow solid. MS (ESI, pos ion.) m/z: 274 (M+1). From the secondfraction was isolated6-chloro-5-(4-trifluoromethyl-phenyl)-pyridazin-3-ylamine.

(b)6-(4-Trifluoromethoxy-phenyl)-5-(4-trifluoromethyl-phenyl)-pyridazin-3-ylamine.A mixture containing6-chloro-5-(4-trifluoromethyl-phenyl)-pyridazin-3-ylamine from step (a)above (531 mg, 1.9 mmol), 4-(trifluoromethoxy)phenyl-boronic acid (889mg, 4.3 mmol, Aldrich), Na₂CO₃ (955 mg, 9.0 mmol, Mallinkrodt) anddichlorobis(triphenylphosphine)palladium (II) (220 mg, 0.3 mmol,Aldrich) in DME (14 mL), H₂O. (6 mL) and EtOH (4 mL) was heated at 80°C. with stirring under N₂ for 15 h. The reaction was allowed to cool toroom temperature, partitioned between EtOAc/H₂O and the layers wereseparated. The aqueous layer was extracted with EtOAc and the combinedorganic layers were evaporated onto SiO₂. Purification by silica gelchromatography with EtOAc/hexanes (0:1→1:0) as eluant afforded the titlecompound as a tan amorphous solid. MS (ESI, pos. ion) nz/z: 400 (M+1).

(c)6-Iodo-3-(4-trifluoromethoxy-phenyl)-4-(4-trifluoromethyl-phenyl)-pyridazine.A mixture of6-(4-trifluoromethoxy-phenyl)-5-(4-trifluoromethyl-phenyl)-pyridazin-3-ylamine(598 mg, 1.5 mmol), cesium iodide (400 mg, 1.5 mmol, Aldrich), iodine(203 mg, 0.8 mmol, Aldrich), CuI (95 mg, 0.5 mmol, Aldrich) and isoamylnitrite (1.2 mL, 8.9 mmol, Aldrich)) in DME (10 mL) was heated at 60° C.for 1 h. The reaction mixture was allowed to cool to room temperatureand filtered. The filtrate was diluted with toluene (50 mL) and washedwith 25% NH₃, 5% Na₂S₂O₃, 5% NaCl and dried over MgSO₄. The solution wasfiltered, evaporated onto SiO₂ and purified by silica gel chromatographywith EtOAc/hexanes (0:1→1:4) as eluant to yield the title compound as acolorless oil. MS (ESI, pos. ion) m/z: 511 (M+1).

(d)7-[6-(4-Trifluoromethoxy-phenyl)-5-(4-trifluoromethyl-phenyl)-pyridazin-3-yloxy]-quinoline.The title compound was prepared analogous to the procedure used toprepare Example 46, using6-iodo-3-(4-trifluoromethoxy-phenyl)-4-(4-trifluoromethyl-phenyl)-pyridazine(377 mg, 0.7 mmol), 7-hydroxyquinoline (130 mg, 0.9 mmol, Acros) and NaH(33 mg, 0.8 mmol, 60% suspension in mineral oil, Aldrich) in DMF (4 mL).Purification by flash silica gel chromatography with EtOAc/hexanes(0:1→7:13) as eluant gave the title compound as a white amorphous solid.MS (ESI, pos ion.) m/z: 528 (M+1).

EXAMPLE 54

N-{3-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-phenyl}-acetamide.A mixture of 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example2(a), Method A), (520 mg, 2.0 mmol), 3-acetamidophenol (320 mg, 2.1mmol, Aldrich) and K₂CO₃ (368 mg, 2.7 mmol) in DMF (10 mL) was heated at80° C. for 8 h. The mixture was allowed to cool to room temperature,poured into H₂O, extracted with EtOAc and the combined organic layerswere evaporated onto SiO₂. Purification by flash silica gelchromatography with EtOAc/hexanes (0:1→2:3) as eluant gave the titlecompound as a white amorphous solid. Mp: 202-205° C. MS (ESI, pos ion.)m/z: 374 (M+1).

EXAMPLE 55

(a) 4-Methyl-quinazolin-8-ol. A mixture of2′-amino-3′-hydroxyacetophenone (500 mg, 3.3 mmol, TCI America) andformamide (1.0 mL, 25 mmol, Aldrich) was heated at 150° C. for 20 minthen 160° C. for 30 min in a microwave synthesizer. The reaction mixturewas diluted with H₂O and the solid was filtered and washed with H₂O. Thesolid was dissolved in MeOH, evaporated onto SiO₂ and purified by flashsilica gel chromatography with EtOAc/hexanes (0: 1→2:3) as eluant togive the title compound as an orange amorphous solid. MS (ESI, pos ion.)m/z: 161 (M+1).

(b)4-Methyl-8-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinazoline.A mixture of 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example2(a), Method A), (102 mg, 0.4 mmol), 4-methyl-quinazolin-8-ol (60 mg,0.4 mmol) and K₂CO₃ (57 mg, 0.4 mmol) in DMF (2 mL) was heated at 80° C.for 1.5 h. The reaction mixture was diluted with H₂O and the solid wasfiltered and washed with H₂O. The solid was dissolved in MeOH,evaporated onto SiO₂ and purified by flash silica gel chromatographywith EtOAc/hexanes (0:1→1:1) as eluant to give the title compound as anoff-white amorphous solid. Mp: 237-240° C. MS (ESI, pos ion.) m/z: 383(M+1).

EXAMPLE 56

(a) 8-Methoxy-quinazolin-2-ylamine. To a solution of3-methoxy-2-nitro-benzaldehyde (14.8 g, 81 mmol, Aldrich) and NH₄Cl (4.4g, 82 mmol, Aldrich) in 80% aq. MeOH (250 mL) was added iron dust (20.5g, 367 mmol, Aldrich) and the reaction mixture was heated at 60° C. withstirring for 2 h. The reaction mixture was allowed to cool to roomtemperature and filtered through a pad of Celite®. The filter cake waswashed with MeOH and the solution was concentrated in vacuum. Theconcentrated aq. solution was extracted with CH₂Cl₂ and the combinedorganic layers were washed with brine and dried over Na₂SO₄.Purification with EtOAc/Hexanes (0:1→1:4) as eluant gave 3.84 g (31%) of2-amino-3-methoxy-benzaldehyde as a yellow oil. This oil was heated at190C for 2.5 h in the presence of guanidine hydrochloride (4.9 g, 51mmol, Aldrich), Na₂CO₃ (5.4 g, 51 mmol) and decalin (55 mL). Thereaction was decanted while hot and the solution was allowed to cool toroom temperature. The resultant precipitate was stirred with hexanes,filtered, washed with hexanes, and dried in vacuum to give the titlecompound as a yellow amorphous solid. MS (ESI, pos ion.) m/z: 176 (M+1).

(b) 2-Amino-quinazolin-8-ol. To a cooled to 0° C. slurry of NaH (1.4 g,35 mmol, 60% suspension in mineral oil, Aldrich) in DMF (100 mL) wasadded ethanethiol (5.0 mL, 67 mmol, Aldrich) and the reaction mixturewas allowed to warm to room temperature. 8-Methoxy-quinazolin-2-ylamine(1.5 g, 8.6 mmol) was then added and the mixture was heated at 80° C.for 14 h. The reaction mixture was allowed to cool to room temperatureand the solvent removed in vacuum. The residue was treated with H₂O, thevolatiles were evaporated in vacuum, and the residue was dissolved inMeOH and evaporated onto SiO₂. Purification by flash silica gelchromatography eluting with 2M NH₃ in MeOH/CH₂Cl₂ (0:1→1:1) gave thetitle compound as a pale-green amorphous solid. MS (ESI, pos ion.) m/z:162 (M+1).

(c)8-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinazolin-2-ylamine.The title compound was prepared analogous to the procedure used inExample 46, using 2-amino-quinazolin-8-ol (217 mg, 1.3 mmol),4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), MethodA), (386 mg, 1.5 mmol), NaH (65 mg, 1.6 mmol, 60% suspension in mineraloil, Aldrich) and DMF (5 mL). Purification by flash silica gelchromatography eluting with EtOAc/hexanes/2MNH₃ in MeOH/CH₂Cl₂(0:1:0:0→2:5:0:0→0:0:0:1→0:0:1:19) gave the title compound as a whiteamorphous solid. Mp: 251-253° C. MS (ESI, pos ion.) m/z: 384 (M+1).

EXAMPLE 57

(a) 4-Butylamino-quinazolin-8-ol. The title compound was preparedanalogous to the procedure used in Example 56(b), usingbutyl-(8-methoxy-quinazolin-4-yl)-amine (1.4 g, 6.1 mmol, preparedaccording to J. Sci. Ind.Research (India) 1956, 15C, 1), ethanethiol(3.0 mL, 40 mmol), NaH (1.2 g, 30 mmol, 60% suspension in mineral oil,Aldrich) and DMF (30 mL). Purification by flash silica gelchromatography eluting with MeOH/CH₂Cl₂ (0:1→2:23) gave impure material.Further purification by flash silica gel chromatography eluting withEtOAc/hexanes (1:3→1:0) gave the title compound as a light-yellowamorphous solid. MS (ESI, pos ion.) m/z: 218 (M+1).

(b)Butyl-{8-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinazolin-4-yl}-amine.The title compound was prepared analogous to the procedure used inExample 46, using 4-butylamino-quinazolin-8-ol (364 mg, 1.7 mmol),4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), MethodA), (485 mg, 1.9 mmol), NaH (86 mg, 2.2 mmol, 60% suspension in mineraloil, Aldrich) and DMF (10 mL). Purification by flash silica gelchromatography eluting with EtOAc/hexanes (0:1→2.3) gave the titlecompound as a light-yellow amorphous solid. MS (ESI, pos ion.) m/z: 440(M+1).

EXAMPLE 58

(a) Diethyl-(8-methoxy-quinazolin-4-yl)-amine. Two reaction vials eachcontaining 4-chloro-8-methoxy-quinazoline (510 mg, 2.6 mmol, preparedaccording to J. Med. Chem. 1994, 37, 2106), diethylamine (1.0 mL, 9.7mmol, Aldrich) and benzene (3 mL) were heated at 150° C. for 10 min in amicrowave synthesizer. The reaction mixtures were combined, thevolatiles were removed in vacuum and the residue was stirred overpentane. The solution was partitioned between EtOAc/satd NaHCO₃ and thelayers were separated. The organic layer was washed with H₂O and brineand dried over Na₂SO₄ to give the title compound as a brown oil. MS(ESI, pos ion.) m/z: 232 (M+1).

(b) 4-Diethylamino-quinazolin-8-ol. The title compound was preparedanalogous to the procedure used in Example 56(b), usingdiethyl-(8-methoxy-quinazolin-4-yl)-amine (1.0 g, 4.4 mmol), ethanethiol(3.8 mL, 51 mmol), NaH (0.9 g, 23 mmol, 60% suspension in mineral oil,Aldrich) and DMF (27 mL). Purification by flash silica gelchromatography eluting with NH₄OH/EtOH/CH₂Cl₂ (0:0:1→1:7:92) gave thetitle compound as a gray amorphous solid. MS (ESI, pos ion.) m/z: 218(M+1).

(c)Diethyl-{8-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinazolin-4-yl}-amine.The title compound was prepared analogous to the procedure used inExample 46, using 4-diethylamino-quinazolin-8-ol (444 mg, 2.0 mmol),4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), MethodA), (820 mg, 3.2 mmol), NaH (106 mg, 2.7 mmol, 60% suspension in mineraloil, Aldrich) and DMF (20 mL). Purification by flash silica gelchromatography eluting with EtOAc/hexanes (0: 1>2.3) gave the titlecompound as a white amorphous solid. Mp: 158-162° C. MS (ESI, pos ion.)m/z: 440 (M+1).

EXAMPLE 59

(a)3-(3-Fluoro-phenyl)-6-methoxy-4-(4-trifluoromethyl-phenyl)-pyridazine.Analogous to the procedure used in Example 51(b), a mixture of3-chloro-6-methoxy-4-(4-trifluoromethyl-phenyl)-pyridazine, (Example51(a)), (0.50 g, 1.7 mmol, 3-fluorobenzeneboronic acid (0.29 g, 2.1mmol, Lancaster), tetrakis(triphenylphosphine)-palladium(0) (0.15 g,0.13 mmol, Lancaster) and Na₂CO₃ (0.69 g, 6.5 mmol, Mallinckrodt) in DME(3.5 mL) and H₂O (1.5 mL) was heated at 150° C. in a microwavesynthesizer for 25 min. The reaction mixture was allowed to cool to roomtemperature, partitioned between H₂O and EtOAc and the aqueous layer wasextracted with EtOAc (3×). The combined organic layers wereconcentrated. Purification by flash chromatography (0→15% EtOAc/hexanes)gave the title compound. MS (ESI, pos. ion) m/z: 349 (M+1).

(b) 6-(3-Fluoro-phenyl)-5-(4-trifluoromethyl-phenyl)-pyridazin-3-ol.Analogous to the method used in Example 51(c), a mixtureof3-(3-fluoro-phenyl)-6-methoxy-4-(4-trifluoromethyl-phenyl)-pyridazine(0.27 g, 0.78 mmol) and HI (47% in H₂O, 2 mL, Aldrich) in MeOH (2 mL)was heated at 75° C. for 16 h. The reaction mixture was allowed to coolto room temperature, diluted with H₂O and filtered. The white solid wasdried in vacuum at room temperature for 4 h to give the title compound.MS (ESI, pos. ion) m/z: 335 (M+1).

(c)6-Chloro-3-(3-fluoro-phenyl)-4-(4-trifluoromethyl-phenyl)-pyridazine.The title compound was prepared analogous to the method used in Example51(d), using6-(3-fluoro-phenyl)-5-(4-trifluoromethyl-phenyl)-pyridazin-3-ol (0.20 g,0.58 mmol) and POCl₃ (3.0 mL, Aldrich). After concentration in vacuum,the residue was stirred with CH₂Cl₂ and satd aq. NaHCO₃ for 3 h. Theaqueous layer was extracted with CH₂Cl₂ (3×) and the combined organiclayers were dried over Na₂SO₄ and filtered through a pad of SiO₂,eluting with EtOAc. The solvent was removed in vacuum to yield the titlecompound as a light-yellow oil. MS (ESI, pos. ion) m/z: 353 (M+1).

(d)7-[6-(3-Fluoro-phenyl)-5-(4-trifluoromethyl-phenyl)-pyridazin-3-yloxy]-quinoline.The title compound was prepared analogous to the procedure in Example 29using6-chloro-3-(3-fluoro-phenyl)-4-(4-trifluoromethyl-phenyl)-pyridazine(0.22 g, 0.62 mmol), 7-hydroxyquinoline (0.099 g, 0.68 mmol, Acros), DMF(3 mL), and NaH (0.033 g, 0.81 mmol, 60% suspension in mineral oil,Aldrich). Purification by flash chromatography (0→50% EtOAc/hexanes)gave the title compound as a white powder. Mp: 165° C., MS (ESI, pos.ion) m/z: 462 (M+1).

EXAMPLE 60

(a) 7-Methoxyquinoline-3-carbaldehyde. A solution of ethyl7-methoxyquinoline-3-carboxylate (2.0 g, 8.6 mmol, prepared according toErickson, E. H. et al. J. Med. Chem. 1979, 22(7), 816-823) in anhydrousTHF (60 mL) was magnetically stirred under N₂ in a −23° C. bath andtreated dropwise with diisobutylaluminum hydride (12 mL, 18 mmol, 1.5 Min toluene, Aldrich). The reaction mixture was stirred at −23° C. for 45min, then treated with an additional aliquot of diisobutylaluminumhydride (12 mL, 18 mmol, 1.5 M in toluene, Aldrich). The reaction wasstirred at −23° C. for 10 min, then quenched by the dropwise addition ofsatd NH₄ Cl (10 mL) followed by the addition of satd aq. solution ofRochelle's salt (100 mL). The mixture was stirred vigorously for 20 minat 25° C. and concentrated in vacuum to ˜110 mL volume. The aqueousphase was extracted with EtOAc (3×100 mL). The combined organic extractswere washed with water (100 mL), satd NaCl (50 mL), dried over Na₂SO₄,filtered and concentrated in vacuum to provide 1.9 g of a mixture of twomajor products. The products were separated by silica gel chromatography(gradient: 0-10% MeOH in EtOAc) to provide an earlier eluting fraction[380 mg, 23%; MS (ESI, pos. ion.) m/z: 192 (M+1)] and a later elutingfraction [745 mg, 46%; MS (ESI, pos. ion.) m/z: 190 (M+1)]. The twoproducts were combined in 2:1 CH₂Cl₂:hexanes (30 mL), magneticallystirred at 25° C., and treated with manganese (IV) oxide (10 g, 115mmol, Aldrich). The suspension was stirred in a 40° C. oil bath for 1 h,allowed to cool to room temperature and filtered through a pad ofCelite®. The pad was washed with CH₂Cl₂ (200 mL) and the combinedfiltrate was concentrated in vacuum to afford the title compound as awhite solid. MS (ESI, pos. ion.) m/z: 188 (M+1).

(b)7-{6-[4-(Trifluoromethyl)phenyl]pyrimidin-4-yloxy}quinoline-3-carbaldehyde.A solution of 7-methoxyquinoline-3-carbaldehyde (790 mg, 4.2 mmol) in48% aq. hydrobromic acid (10 mL, Aldrich) was distributed equally intotwo separate microwave-safe, 10-mL, glass reaction vessels equipped withstir bars. The reaction vessels were heated in a microwave synthesizerat 180° C. for 15 min each, then recombined and concentrated in vacuumto afford a tan solid (1.1 g). The solid was treated with4-chloro-6-[4-(trifluoromethyl)-phenyl]pyrimidine, (Example 2(a), MethodA), (1.2 g, 4.6 mmol), methylsulfoxide (10 mL, Aldrich), and cesiumcarbonate (6.8 g, 21 mmol, Aldrich). The reaction mixture wasmagnetically stirred under N₂ in an 80° C. oil bath for 18 h, thenallowed to cool to room temperature and partitioned between EtOAc (200mL) and water (200 mL). The aqueous phase was extracted with EtOAc(2×100 mL) and the combined organic phases were washed with water (100mL), satd NaCl (50 mL), dried over Na₂SO₄, filtered and concentrated invacuum. Purification by silica gel chromatography (gradient: 10-35%EtOAc/hexanes, followed by 35% EtOAc/hexanes) provided the titlecompound as an off-white solid. MS (ESI, pos. ion.) m/z: 396 (M+1).

(c)(7-{6-[4-(Trifluoromethyl)phenyl]pyrimidin-4-yloxy}-3-quinolyl)methan-1-ol.A suspension of7-{6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yloxy}quinoline-3-carbaldehyde(210 mg, 0.53 mmol) in EtOH (20 mL) was stirred at 0° C. and treatedwith sodium borohydride (20 mg, 0.53 mmol, Aldrich) resulting in ayellow solution. The reaction mixture was allowed to stir at 25° C. for5 min, then quenched with water (5 mL) and concentrated in vacuum. Theresidue was partitioned between EtOAc (100 mL) and 10% Na₂CO₃ (50 mL).The organic layer was separated and washed with 10% Na₂CO₃ (50 mL), satdNaCl (50 mL), dried over Na₂SO₄, filtered and concentrated in vacuum.Purification by silica gel chromatography (gradient: 75-95%EtOAc/hexanes) provided the title compound as a white solid. Mp: 181° C.MS (ESI, pos. ion.) m/z: 398 (M+1). Anal. Calcd for C₂₁H₁₄F₃N₃O₂: C,63.48; H, 3.55; N, 10.58; F, 14.34. Found: C, 63.43; H, 3.62; N, 10.46;F, 14.23.

EXAMPLE 61

1-(7-{6-[4-(Trifluoromethyl)phenyl]pyrimidin-4-yloxy}-3-quinolyl)ethan-1-ol.A solution of7-{6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yloxy}quinoline-3-carbaldehyde,(Example 60b), (220 mg, 0.56 mmol) in anhydrous THF (10 mL) wasmagnetically stirred under N₂ in a −78° C. bath while methylmagnesiumbromide (0.22 mL, 0.66 mmol, 3.0 M in Et₂O, Aldrich) was added quickly.The reaction mixture was stirred at −78° C. for 5 min, then treated withsatd NH₄Cl (5 mL). The bath was removed and the mixture was stirred for5 min, then diluted with EtOAc (60 mL) and washed with satd NH₄Cl (20mL), water (20 mL), satd NaHCO₃ ₍20 mL), satd NaCl (20 mL), dried overNa₂SO₄, filtered and concentrated in vacuum. Purification by silica gelchromatography (gradient: 60-85% EtOAc in hexanes) provided the titlecompound as an off-white solid. Mp: 156-157° C. MS (ESI, pos. ion.) m/z:412 (M+1). Anal. Calcd for C₂₂H₁₆F₃N₃O₂: C, 64.23; H, 3.92; N, 10.21; F,13.85. Found: C, 63.99; H, 4.05; N, 10.01; F, 13.63.

EXAMPLE 62

(a) Methyl 7-hydroxyquinoline-3-carboxylate. A solution of ethyl7-methoxyquinoline-3-carboxylate (500 mg, 2.1 mmol, prepared accordingto Erickson, E. et al. J. Med. Chem. 1979, 22(7), 816-823) in 48% aq.hydrobromic acid (2.5 mL, Aldrich) was added to a microwave-safe, 10-mL, glass reaction vessel equipped with a stir bar. The reactionvessel was heated in a microwave synthesizer at 160° C. for 20 min. Anadditional aliquot of 48% aq. hydrobromic acid (1.0 mL, Aldrich) wasadded and the mixture heated at 160° C. for an additional 35 min. Theresulting solid precipitate was collected by filtration, washed withwater (10 mL) and dried in vacuum at 60° C. to afford a solid (255 mg).The filtrate was concentrated in vacuum to afford an additional 260 mgproduct. The solid products were combined in MeOH (250 mL), stirred inan ice bath and treated in portions with diazomethane (80 mL total, 0.2M in Et₂O, prepared according to Black, T. H. Ald. Acta 1983, 16(1),3-10). The reaction was followed closely by HPLC-MS to avoidover-alkylation. The reaction mixture was concentrated in vacuum toprovide the title compound. MS (ESI, pos. ion.) m/z: 204 (M+1).

(b) Methyl7-{6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yloxy}quinoline-3-carboxylate.Methyl 7-hydroxyquinoline-3-carboxylate (350 mg, 1.7 mmol) was treatedwith 4-chloro-6-[4-(trifluoromethyl)-phenyl]pyrimidine, (Example 2(a),Method A), (490 mg, 1.9 mmol), methylsulfoxide (10 mL, Aldrich), andcesium carbonate (1.7 g, 5.2 mmol, Aldrich). The reaction mixture wasmagnetically stirred under N₂ in a 50° C. oil bath for 5 h, then allowedto cool to room temperature and partitioned between EtOAc (300 mL) andwater (150 mL). The organic phase was washed with water (2×100 mL), satdNaCl (50 mL), dried over Na₂SO₄, filtered and concentrated in vacuum.Purification by silica gel chromatography (gradient: 10-25% EtOAc inhexanes, followed by 25% EtOAc in hexanes) provided the title compoundas a white solid; Mp: 216-217° C. MS (ESI, pos. ion.) m/z: 426 (M+1).

EXAMPLE 63

2-(7-{6-[4-(Trifluoromethyl)phenyl]pyrimidin-4-yloxy}-3-quinolyl)propan-2-ol.A solution of methyl7-{6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yloxy}quinoline-3-carboxylate,(Example 62b), (150 mg, 0.35 mmol) in anhydrous THF (10 mL) wasmagnetically stirred in a 0° C. bath and treated dropwise withmethyllithium (0.63 mL, 1.0 mmol, 1.6 M in Et₂O, Aldrich). Afteraddition was complete, the reaction was quenched with satd NH₄Cl (5 mL),then diluted with EtOAc (120 mL) and washed with water (30 mL). Theorganic phase was washed with satd NaCl (10 mL), dried over Na₂SO₄,filtered and concentrated in vacuum. Purification by silica gelchromatography (gradient: 50-60% EtOAc/hexanes) provided the titlecompound as a yellow amorphous solid. MS (ESI, pos. ion.) m/z: 426(M+1).

EXAMPLE 64

(a) 2H,3H-Benzo[e]1,4-dioxan-6-ol. A solution of2,3-dihydro-1,4-benzodioxin-6-ylacetate (1.35 g, 6.95 mmol, preparedaccording to Besson, T. et al. Tetrahedron 1995, 55, 3197-3204) in MeOH(20 mL) was treated with 1 N NaOH (5 mL) and stirred at 25° C. for 30min. The reaction mixture was concentrated in vacuum to a volume of ˜5mL and acidified to pH 1 with 1 N HCl. The aqueous mixture was extractedwith EtOAc (3×50 mL). The combined organic extracts were washed withwater (50 mL), satd NaCl (50 mL), dried over MgSO₄, filtered andconcentrated in vacuum to afford the title compound as a viscous, brownoil. MS (ESI, pos. ion.) m/z: 153 (M+1).

(b)6-{6-[4-(Trifluoromethyl)phenyl]pyrimidin-4-yloxy}-2H,3H-benzo[e]1,4-dioxane.A solution of 2H,3H-benzo[e]1,4-dioxan-6-ol (300 mg, 2.0 mmol) and4-chloro-6-[4-(trifluoromethyl)-phenyl]pyrimidine, (Example 2(a), MethodA), (560 mg, 2.2 mmol) in acetonitrile (10 mL) was treated with1,8-diazabicyclo[5.4.0]undec-7-ene (0.60 mL, 4.0 mmol, Aldrich). Thereaction mixture was magnetically stirred in an 85° C. oil bath, under areflux condenser, for 1 h, then allowed to cool to room temperature. Themixture was diluted with EtOAc (75 mL), washed with 1 N HCl (30 mL),satd NaHCO₃ (30 mL), water (30 mL), satd NaCl (20 mL), dried overNa₂SO₄, filtered and concentrated in vacuum. Purification by silica gelchromatography (gradient: 10-20% EtOAc/hexanes, followed by 20%EtOAc/hexanes) provided the title compound as a white solid. Mp:163.6-163.7° C. MS (ESI, pos. ion.) m/z: 375 (M+1). Anal. Calcd forC₁₉H₁₃F₃N₂O₃: C, 60.97; H, 3.50; N, 7.48; F, 15.23. Found: C, 60.56; H,3.36; N, 7.29; F, 15.56.

EXAMPLE 65

4-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine.To a solution of 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine,(Example 2(a), Method A), ((0.13 g, 0.5 mmol) and2-amino-4-hydroxybenzothiazole (83 mg, 0.5 mmol, Astatech) in DMF (1 mL)was added potassium carbonate (0.14 g, 1 mmol) and the mixture washeated at 80° C. for 16 h with sirring. The reaction mixture was allowedto cool to room temperature and partitioned between EtOAc and brine. Thelayers were separated and the aq. layer was extracted with EtOAc. Thecombined organic extracts were dried over Na₂SO₄, filtered andconcentrated under vacuum. Purification of the residue by silica gelchromatography (2:1 hexanes: EtOAc) provided the title compound as awhite solid. MS (ESI, pos. ion) m/z: 389 (M+1). Mp: 232.0-233.5° C.Anal. Calcd for C₁₈H₁₁F₃N₄O_(S): C, 55.67; H, 2.85; N, 14.43; S, 8.26.Found: C, 55.52; H, 3.08; N, 14.23; S, 8.36.

EXAMPLE 66

N-{4-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide.A mixture of4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine,(Example 65), (97 mg, 0.25 mmol) and acetic anhydride (0.24 mL, 2.5mmol) was heated in a 105° C. oil bath for 8 h. The solvent wasevaporated and the solid that formed was recrystallized fromEtOAc/hexanes, and dried under vacuum to give the title compound. MS(ESI, pos. ion) m/z: 431 (M+1). Mp: 219.0-220.5° C. Anal. Calcd forC₂₀H₁₃F₃N₄O₂S0.75H₂O: C, 54.11; H, 3.29; N, 12.62; S, 7.22. Found: C,54.12; H, 3.07; N, 12.61; S, 7.30.

EXAMPLE 67

2-Hydroxy-N-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-propionamide.A mixture of (+/−)-2-acetoxypropionic acid (56 uL, 0.5 mmol, Fluka) inthionyl chloride (1 mL) was heated at reflux for 3 h. After evaporationof the solvent, the residue was dissolved in THF, and treated with4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine,(Example 65), (97 mg, 0.25 mmol) and2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine,polymer bound (BEMP resin) (0.17 g, 0.38 mmol, Aldrich). The reactionmixture was stirred at 25° C. for 16 h. The insoluble material wasfiltered off and washed with CH₂Cl₂. The filtrate was concentrated andthen dissolved in MeOH. Potassium carbonate (69 mg, 0.5 mmol) was addedand the reaction mixture was stirred at 25° C. for 2 h. The solvent wasevaporated in vacuum and to the residue was added CH₂Cl₂ (30 mL). Afterstirring for 5 min, the precipitate was collected by filtration andpurified by silica gel chromatography (3:1 of EtOAc/hexanes) to give thetitle compound. MS (ESI, pos. ion) m/z: 461 (M+1).

EXAMPLE 68

(a) (S)-Acetic acid1-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylcarbamoyl}-ethylester. According to the procedure described in Example 67, the titlecompound was prepared by using4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine,(Example 65), (0.39 g, 1 mmol), (S)-(−)-2-acetoxypropionyl chloride(0.25 mL, 2 mmol, Aldrich) and2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine,polymer bound (BEMP resin) (0.68 g, 1.5 mmol, Aldrich) in THF (10 mL).Purification by silica gel chromatography (1:3 of EtOAc/hexanes)provided the title compound. MS (ESI, pos. ion) m/z: 503 (M+1).

(b)2-(S)-Hydroxy-N-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-propionamide.To a solution of (S)-acetic acid1-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylcarbamoyl}-ethylester (0.19 g, 0.38 mmol) in MeOH (4 mL) was added potassium carbonate(0.11 g, 0.76 mmol) and the mixture was stirred at 25° C. for 2 h. Thesolvent was evaporated in vacuum and the residue was purified by silicagel chromatography (EtOAc/hexanes=1:2) to give the title compound as awhite solid. Chiral LC purification on Chiralpak AD column with80:20:0.2 of hexanes: IPA: diethylamine gave the desired isomer as awhite solid. MS (ESI, pos. ion) m/z: 461 (M+1).

EXAMPLE 69

2-(R)-Hydroxy-N-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-propionamide.The chiral LC separation of the reaction product of Example 68(b) alsogave small amount of the (R¹)-isomer as a white solid. MS (ESI, pos.ion) m/z: 461 (M+1).

EXAMPLE 70

(a) 2-Amino-benzene-1,3-diol hydrochloride. To a solution of2-nitroresorcinol (0.79 g, 5 mmol, Aldrich) in EtOH (50 mL) was added10% palladium on carbon (0.26 g) and cond HCl (0.4 mL), and the reactionmixture was stirred under 1 atm of H₂ for 3 h. The mixture was filteredthrough a pad of Celite®, the filter cake was washed with EtOH, and thefiltrate was concentrated in vacuum to give the title compound as anoff-white solid, which was used in the next step without additionalpurification. MS (ESI, pos. ion) m/z: 126 (M+1).

(b) 2-Amino-benzooxazol-4-ol. 2-Amino-benzene-1,3-diol hydrochloride(crude, 5 mmol) was dissolved in water (3 mL) and neutralized withNaHCO₃ (0.42 g, 5 mmol). Cyanogen bromide (0.48 g, 4.5 mmol, Aldrich)was then added portion wise to the solution, with stirring at roomtemperature. The mixture was left to stand at 25° C. for 2 days. Theinsoluble material was filtered off and the filtrate was neutralizedwith aq. Na₂CO₃ to pH 5. The precipitate was collected by filtration,washed with water (1 mL) and dried under vacuum to give the titlecompound as a tan solid. MS (ESI, pos. ion) m/z: 151 (M+1).

(c)4-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzooxazol-2-ylamine.This material was prepared according to the method described in Example3 using 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a),Method A), (0.78 g, 3 mmol), 2-amino-benzooxazol-4-ol (0.3 g, 2 mmol),and K₂CO₃ (0.83 g, 6 mmol) in DMF (6 mL). The precipitate formed wascollected by filtration, washed with ether (4 mL) and dried to give thetitle compound as an off-white solid. MS (ESI, pos. ion) m/z: 373 (M+1).Mp: 235.0-247.9° C.

EXAMPLE 71

N-{4-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzooxazol-2-yl}-acetamide.This material was prepared according to the method described in Example66 using4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzooxazol-2-ylamine,(Example 70(c)), (0.27 g, 0.72 mmol) and acetic anhydride (82 uL, 0.87mmol) in pyridine (3 mL). Purification by silica gel chromatography(1:1.5 of EtOAc/hexanes) provided the title compound as a white solid.MS (ESI, pos. ion) m/z: 415 (M+1). Mp: 205.1-205.2° C.

EXAMPLE 72

(a) 2-Methylamino-quinolin-8-ol. This material was prepared according tothe method described in Example 5(a) using 2-chloro-quinolin-8-ol,(Example 2(a), Method B), (0.18 g, 1 mmol) and methylamine (10 mL, 20mmol, 2M in THF, ALdrich) in dioxane (3 mL). Recrystallization fromMeOH/H₂O provided the title compound as a light-yellow solid. MS (ESI,pos. ion) m/z: 175 (M+1).

(b)Methyl-{8-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinolin-2-yl}-amine.This material was prepared according to the method described in Example3 using 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a),Method A), (0.22 g, 0.85 mmol), 2-methylamino-quinolin-8-ol (0.12 g,0.71 mmol), and potassium carbonate (0.2 g, 1.4 mmol) in DMF (1.5 mL).Purification by silica gel chromatography (5:1 hexanes: EtOAc) providedthe title compound as a white solid. MS (ESI, pos. ion) m/z: 397 (M+1).Mp: 163.0-165.0° C. Anal. Calcd for C₂₁H₁₅F₃N₄O.0.25 H₂O: C, 62.92; H,3.90; N, 13.98. Found: C, 62.98; H, 3.83; N, 13.77.

EXAMPLE 73

N-{8-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinolin-2-yl}-acetamide.This material was prepared according to the method described in Example66 using8-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinolin-2-ylamine,(Example 2(d), Method B), (0.79 g, 2.1 mmol) and acetic anhydride (2.5mL, 2.6 mmol). Purification by silica gel chromatography (2:1 hexanes:EtOAc) provided the title compound as a white solid. MS (ESI, pos. ion)m/z: 425 (M+1). Mp: 203.8-206.0° C. Anal. Calcd for C₂₂H₁₅F₃N₄O₂: C,62.26; H, 3.56; N, 13.20. Found: C, 62.28; H, 3.51; N, 13.15.

EXAMPLE 74

(a) 8-Benzyloxy-quinolin-2-ylamine. To 2-amino-8-hydroxyquinoline (0.96g, 6 mmol, Fluka) dissolved in acetone (30 mL) was added potassiumcarbonate (1.2 g, 9 mmol) and the reaction mixture was stirred at 25° C.for 10 min. Benzyl bromide (1.1 mL, 9 mmol, Aldrich) was then addeddropwise and the reaction mixture was heated at 50° C. for 16 h. Aftercooling to room temperature, the precipitate was filtratered, washedwith acetone and water, and dried under vacuum to give the titlecompound as an off-white solid. MS (ESI, pos. ion) m/z: 251 (M+1).

(b) N-(8-Benzyloxy-quinolin-2-yl)-methanesulfonamide. To8-benzyloxy-quinolin-2-ylamine suspended in THF (6 mL) and DMF (1 mL)was added NaH (0.14 g, 3.6 mmol, 60% suspension in mineral oil,Aldrich). After stirring for 10 min at 25° C., methanesulfonyl chloride(0.26 mL, 3.3 mmol, Aldrich) was added. The reaction mixture was stirredat room temperature for 16 h and then partitioned between EtOAc and 10%citric acid. The aqueous layer was separated, saturated with NaCl andextracted with a mixture of MeOH and EtOAc. The combined organic layerswere washed with brine, dried over Na₂SO₄ and concentrated in vacuum.Purificaton of the residue by silica gel chromatography (1.5:1 hexanes:EtOAc) provided the title compound as an off-white solid. MS (ESI, pos.ion) m/z: 329 (M+1).

(c) N-(8-Hydroxy-quinolin-2-yl)-methanesulfonamide. ToN-(8-benzyloxy-quinolin-2-yl)-methanesulfonamide (0.18 g, 0.54 mmol)suspended in EtOH (2.5 mL) was added 10% palladium on carbon (0.18 g,Aldrich), followed by cyclohexadiene (0.51 mL, 5.4 mmol, Aldrich). Thereaction mixture was stirred at 25° C. for 2 h, filtered through a padof Celite®, and the filtrate was concentrated in vacuum to give thetitle compound as an off-white solid. MS (ESI, pos. ion) m/z: 239 (M+1).

(d)N{8-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinolin-2-yl)}-methanesulfonamide.This material was prepared according to the method described in Example3 using 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a),Method A), (0.18 g, 0.69 mmol),N-(8-hydroxy-quinolin-2-yl)-methanesulfonamide (0.11 g, 0.46 mmol), andpotassium carbonate (0.13 g, 0.92 mmol) in DMF (0.5 mL). Purification bysilica gel chromatography (1:1 hexanes: EtOAc) provided the titlecompound as a white solid. MS (ESI, pos. ion) m/z: 461 (M+1). Mp:216.7-219.7° C. Anal. Calcd for C₂₁H₁₅F₃N₄O₃S: C, 54.78, H. 3.28; N.12.17, S. 6.96. Found: C, 54.69; H. 3.35, N. 12.06, S. 7.11.

EXAMPLE 75

(a) 2-(2-Hydroxy-ethylamino)-quinolin-8-ol. This material was preparedaccording to the method described in Example 5(a) using2-chloro-quinolin-8-ol, (Example 2(a), Method B), (0.12 g, 0.67 mmol)and ethanolamine (0.8 mL, 13 mmol, Aldrich) in dioxane (2 mL).Recrystallization from MeOH/H₂O provided the title compound as a yellowsolid. MS (ESI, pos. ion) m/z: 205 (M+1).

(b)2-{8-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinolin-2-ylamino}-ethanol.This material was prepared according to the method described in Example3 using 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a),Method A), (0.14 g, 0.56 mmol), 2-(2-hydroxy-ethylamino)-quinolin-8-ol(95 mg, 0.47 mmol), and potassium carbonate (0.16 g, 1.1 mmol) in DMF(1.5 mL). Purification by silica gel chromatography (1:1 hexanes: EtOAc)provided the title compound as a white solid. MS (ESI, pos. ion) m/z:427 (M+1). Mp:157.5-160.5° C. Anal. Calcd for C₂₂H₁₇F₃N₄O₂: C, 61.97; H,4.02; N, 13.14. Found: C, 61.93; H, 4.02; N, 13.17.

EXAMPLE 76

(a) [2-(8-Hydroxy-quinolin-2-ylamino)-ethyl]-carbamic acid tert-butylester. This material was prepared according to the method described inExample 5(a) using 2-chloro-quinolin-8-ol (0.18 g, 1 mmol) andtert-butyl N-(2-aminoethyl)carbamate (3.2 g, 20 mmol, Aldrich) indioxane (3 mL). Recrystallization from MeOH/H₂O provided the titlecompound as a tan solid. MS (ESI, pos. ion) m/z: 304 (M+1).

(b)(2-{8-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinolin-2-ylamino}-ethyl)-carbamicacid tert-butyl ester. This material was prepared according to themethod described in Example 3 using4-chloro-6-(4-trifluoromethyl-phenyl)-pyridine, (Example 2(a), MethodA), (0.17 g, 0.65 mmol),[2-(8-hydroxy-quinolin-2-ylamino)-ethyl]-carbamic acid tert-butyl ester(0.16, 0.54 mmol), and potassium carbonate (0.15 g, 1.1 mmol) in DMF(1.5 mL). Purification by silica gel chromatography (3:1 hexanes: EtOAc)provided the title compound as a white solid. MS (ESI, pos. ion) m/z:526 (M+1).

(c)N1-{8-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinolin-2-yl}-ethane-1,2-diaminetrifluoroacetate. To(2-{8-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinolin-2-ylamino}-ethyl)-carbamicacid tert-butyl ester (60 mg, 0.11 mmol) suspended in CH₂Cl₂ (1 mL) wasadded dropwise trifluoroacetic acid (0.5 mL, Aldrich). The reactionmixture was stirred at 25° C. for 2 h, the solvent was evaporated andthe residue was recrystallized from MeOH to give the title compound as awhite solid. MS (ESI, pos. ion) m/z: 426 (M+1). Mp: 161.0-163.0° C.Anal. Calcd for C₂₂H₁₈F₃N₅O2CF₃CO₂H2H₂O: C, 45.29; H, 3.51; N, 10.16.Found: C, 45.24; H, 3.51; N, 10.06.

EXAMPLE 77

(a) Acetic acid{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylcarbamoyl}-methylester. According to the procedure described in Example 67, the titlecompound was prepared by using4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine,(Example 65), (0.39 g, 1 mmol), acetoxyacetyl chloride (0.22 mL, 2 nmol,Aldrich) and2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine,polymer bound (BEMP resin) (0.68 g, 1.5 mmol) in THF (10 mL).Purification by silica gel chromatography (1:3 of EtOAc/hexanes)provided the title compound as a white solid. MS (ESI, pos. ion) m/z:489 (M+1).

(b)2-Hydroxy-N-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide.This material was prepared according to the procedure described inExample 68(b) using acetic acid{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylcarbamoyl}-methylester (0.1 g, 0.2 mmol) and potassium carbonate (57 mg, 0.4 mmol) in amixture of MeOH (2 mL) and CH₂Cl₂ (2 mL). Purification by silica gelchromatography (1:1.5 of EtOAc/hexanes) provided the title compound as awhite solid. MS (ESI, pos. ion) m/z: 447 (M+1).

EXAMPLE 78

(a) Acetic acid1-methyl-1-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylcarbamoyl}-ethylester. To4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine,(Example 65), (0.39 g, 1 mmol) suspended in dioxane (3 mL) was addedtriethylamine (0.27 mL, 2 mmol, Aldrich), followed by1-chlorocarbonyl-1-methyl-ethyl acetate (0.29 mL, 2 mmol). The reactionmixture was heated at 100° C. for 16 h, allowed to cool to roomtemperature and partitioned between EtOAc and brine. The layers wereseparated and the aqueous layer extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated undervacuum. Purification of the residue by silica gel chromatography (3:1hexanes: EtOAc) provided the title compound as a white foam. MS (ESI,pos. ion) m/z: 517 (M+1).

(b)2-Hydroxy-2-methyl-N-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-propionamide.This material was prepared according to the procedure described inExample 68(b) using acetic acid1-methyl-1-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylcarbamoyl}-ethylester (0.5 g, 1 mmol) and potassium carbonate (0.27 g, 1.9 mmol) in MeOH(10 mL). Purification by silica gel chromatography (1:3 ofEtOAc/hexanes) provided the title compound as a white solid. MS (ESI,pos. ion) m/z: 475 (M+1). Mp: 213.1-215.6° C.

EXAMPLE 79

Acetic acid{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylcarbamoyl}-methylester. This material was prepared according to the procedure describedin Example 78(a) using4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine,(Example 65), (0.36 g, 0.9 mmol), O-acetyl mandelic acid (0.41 mL, 1.8mmol, Heico Chemicals, Inc.) and triethylamine (0.25 mL, 1.8 mmol) indioxane (3 mL). Purification by silica gel chromatography (3:1 hexanes:EtOAc) provided the title compound as a light-yellow foam. MS (ESI, pos.ion) m/z: 565 (M+1). Mp: 118.6-138.4° C.

EXAMPLE 80

2-Hydroxy-2-phenyl-N-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide.This material was prepared according to the procedure described inExample 68(b) using acetic acidphenyl-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylcarbamoyl}-methylester, (Example 79), (0.44 g, 0.78 mmol) and potassium carbonate (0.22g, 1.6 mmol) in MeOH (8 mL). Purification by silica gel chromatography(1:2 of EtOAc/hexanes) provided the title compound as a white solid. MS(ESI, pos. ion) m/z: 523 (M+1). Mp: 197.7-205.4° C.

EXAMPLE 81

2-Phenyl-N-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide.According to the procedure described in Example 67, the title compoundwas prepared by using4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine,(Example 65), (0.19 g, 0.5 mmol), phenylacetyl chloride (0.13 mL, 1mmol, Aldrich), and2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine,polymer bound (BEMP resin) (0.34 g, 0.75 mmol) in THF (5 mL).Purification by silica gel chromatography (1:4 of EtOAc/hexanes)provided the title compound as a white solid. MS (ESI, pos. ion) m/z:507 (M+1). Mp: 188.6-191.0° C.

EXAMPLE 82

N-{4-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-propionamide.According to the procedure described in Example 67, the title compoundwas prepared by using4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine,(Example 65), (0.19 g, 0.5 mmol), propionyl chloride (87 uL, 1 mmol,Aldrich), and2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine,polymer bound (BEMP resin), (0.34 g, 0.75 mmol) in THF (5 mL).Purification by silica gel chromatography (1:4 of EtOAc/hexanes)provided the title compound as a white solid. MS (ESI, pos. ion) m/z:445 (M+1). Mp: 196.9-197.6° C.

EXAMPLE 83

(a)2-Chloro-N-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide.To a mixture of4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine,(Example 65), (0.39 g, 1 mmol) and pyridine (97 uL, 1.2 mmol) in toluene(3.5 mL) was added chloroacetyl chloride (96 uL, 1.2 mmol, Aldrich) at10° C. The reaction mixture was stirred at 10° C. for 1 h, then at 25°C. for 16 h and partitioned between EtOAc and water. The layers wereseparated and the aqueous layer was extracted with EtOAc. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuum to give the title compound. MS (ESI, pos. ion)m/z: 465 (M+1).

(b)2-Dimethylamino-N-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamidetrifluoroacetate. To2-chloro-N-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide(0.15 g, 0.33 mmol) suspended in CH₂Cl₂ (1.5 mL) was added 2 M solutionof dimethylamine in MeOH (0.41 mL, 0.82 mmol, Aldrich) and the reactionmixture was stirred at 25° C. for 16 h. The solvent was evaporated andthe residue was purified by silica gel chromatography (1:1 ofEtOAc/hexanes), followed by preparative HPLC separation (10-90% 0.1% TFAacetonitrile in 0.1% TFA water for 20 min) to give the title compound asan off-white solid. MS (ESI, pos. ion) m/z: 474 (M+1). Mp: 67.9-68.0° C.

EXAMPLE 84

2-Morpholin-4-yl-N-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide.This material was prepared according to the procedure described inExample 83(b) using2-chloro-N-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide,(Example 83(a)), (0.17 g, 0.33 mmol) and morpholine (72 uL, 0.82 mmol,Aldrich) in CH₂Cl₂ (1.5 mL). Purification by silica gel chromatography(1:1 of EtOAc/hexanes) provided the title compound as a white solid. MS(ESI, pos. ion) m/z: 516 (M+1). Mp:177.8-181.7° C.

EXAMPLE 85

(a)2,2,2-Trifluoro-N-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide.A suspension of4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine,(Example 65), (0.15 g, 0.38 mmol) and pyridine (33 uL, 0.41 mmol) inCH₂Cl₂ (2 mL) was treated with trifluoroacetic anhydride (58 uL, 0.41mmol, Aldrich) at 0° C. under nitrogen atmosphere. The reaction mixturewas stirred at 0° C. for 2 h and partitioned between CH₂Cl₂ and brine.The layers were separated and the aqueous layer was extracted withEtOAc. The combined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuum to give the title compound as a white solid. MS(ESI, pos. ion) m/z: 485 (M+1).

(b)Methyl-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-amine.To2,2,2-trifluoro-N-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide(0.18 g, 0.37 mmol) dissolved in DMF (1 mL) was added iodomethane (51uL, 0.82 mmol, Aldrich) and cesium carbonate (0.25 g, 0.78 mmol,Aldrich). The reaction mixture was heated at 70° C. for 22 h, allowed tocool to room temperature and partitioned between EtOAc and brine. Thelayers were separated and the aqueous layer was extracted with EtOAc.The combined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuum. Purification of the residue by silica gelchromatography (1:1 of EtOAc/hexanes) provided the title compound as anoff-white solid. MS (ESI, pos. ion) m/z: 403 (M+1).

EXAMPLE 86

2-Bromo-4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazole.To a suspension of anhydrous CuBr₂ (0.54 g, 2.4 mmol,Aldrich) in dryacetonitrile (4 mL) was added isoamyl nitrite (0.4 mL, 3 mmol, Aldrich)dropwise and the mixture was stirred at room temperature for 10 min.4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine(0.78 g, 2 mmol) was added in small portions and the reaction mixturewas stirred at 25° C. for 1 h, and then heated at 65° C. for 1.5 h. Themixture was filtered through a pad of Celite® and washed withacetonitrile. The filtrate was concentrated in vacuum and purified bysilica gel chromatography (1:6 of EtOAc/hexanes) to give the titlecompound as a white solid. MS (ESI, pos. ion) nvz: 453 (M+1).

EXAMPLE 87

2-{4-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamino}-ethanol.To2-bromo-4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazole,(Example 86), (90 mg, 0.2 mmol) dissolved in dioxane (1 mL) was addedethanolamine (0.06 mL, 1 mmol, Aldrich). The reaction mixture was heatedin microwave synthesizer at 200° C. for 10 min, allowed to cool to roomtemperature and evaporated in vacuum. Purification of the residue bysilica gel chromatography (1:1 of EtOAc/hexanes) provided the titlecompound as a white solid. MS (ESI, pos. ion) m/z: 433 (M+1).

EXAMPLE 88

N-{4-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}methanesulfonamide. To a solution of4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine,(Example 65), (0.19 g, 0.5 mmol) in DMF (1.5 mL) was addedmethanesulfonyl chloride (92 uL, 1.2 mmol) and triethylamine (0.2 mL,1.5 mmol). The reaction mixture was stirred at 60C for 1 h, at 110° C.for 16 h, allowed to cool to room temperature and partitioned betweenEtOAc and brine. The layers were separated and the aqueous layer wasextracted with EtOAc. The combined organic layers were dried overNa₂SO₄, filtered and concentrated under vacuum. Purification of theresidue by silica gel chromatography (1:1 of EtOAc/hexanes) provided thetitle compound as an off-white solid. MS (ESI, pos. ion) m/z: 467 (M+1).

EXAMPLE 89

(a)3-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzene-1,2-diaminetrifluoroacetate. K₂CO₃ (138 mg, 1 mmol) was added to a solution of2,3-diamino-phenol (100 mg, 0.81 mmol, Aldrich),4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), MethodA), (202 mg, 0.80 mmol) and DMF (2 mL), and the resulting mixture wasirradiated at 180° C. for 10 min in a microwave synthesizer. The solventwas removed under reduced pressure and purified by prep. LC (10-90%CH₃CN/H₂O modified with 0.1% TFA) to give the title compound as a blackoil. MS (ESI, pos. ion.) m/z: 347 (M+1).

(b)4-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-1H-benzoimidazole. Asolution of3-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzene-1,2-diamine(50 mg, 0.14 mmol), EtOH (1 mL), ethyl formate (1 mL, Aldrich) and HOAc(50 uL) was irradiated at 160° C. for 10 min in a microwave synthesizer.The reaction mixture was left at room temperature for 2 h and theresulting precipitate was filtered, washed with ethyl formate and driedunder vacuum to give the title compound as an off-white solid. MS (ESI,pos. ion.) m/z: 357 (M+1).

EXAMPLE 90

4-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-1H-benzoimidazol-2-ylaminetrifluoroacetate. Cyanogen bromide (16 mg, 0.15 mmol, Aldrich) was addedto a solution of3-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzene-1,2-diamine,(Example 89), (50 mg, 0.14 mmol) in EtOH (2 mL). After stirring for 3days the solvent was removed under reduced pressure and the mixture waspurified by prep. LC (10-90% CH₃CN/H₂O modified with 0.1% TFA) to givethe title compound as a white solid. MS (ESI, pos. ion.) m/z: 372 (M+1).

EXAMPLE 91

2-Iodo-4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazoletrifluoroacetate and4-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazoletrifluoroacetate. A mixture of4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine,(Example 65), (100 mg, 0.26 mmol), isoamyl nitrite (0.21 mL, 1.6 mmol,Aldrich), CsI (68 mg, 0.26 mmol, Aldrich), I₂ (33 mg, 0.13 mol,Aldrich), CuI (15 mg, 0.079 mmol, Aldrich) and DME (5 mL) was heated at65° C. for 1.5 h. The mixture was allowed to cool to room temperatureand the solvent was removed under reduced pressure. The resultingmixture was purified by prep. LC (10-90% CH₃CN/H₂O modified with 0.1%TFA) to give2-iodo-4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazoleas a white solid [(30 mg, 23%), MS (ESI, pos. ion.) m/z: 500 (M+1)] and4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazole as abrown solid [MS (ESI, pos. ion.) m/z: 374 (M+1)].

EXAMPLE 92

2-Chloro-4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazole.The title compound was prepared in an analogous manner to the conditionsof Example 91 by reacting4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine(Example 65) with CsCl and CuCl. MS (ESI, pos. ion.) m/z: 408 (M+1).

EXAMPLE 93

2-Pyridin-4-yl-4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazoletrifluoroacetate. A mixture of2-iodo-4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazole,(Example 91), (35 mg, 0.070 mmol), 4-pyridyl boronic acid (13 mg, 0.11mmol), Pd(PPh₃)₄ (12 mg, 0.010 mmol) Na₂CO₃ (0.20 mL, 2M aq. solution)and dioxane (1 mL) was irradiated at 200° C. for 10 min in a microwavesynthesizer. The solvent was removed under reduced pressure, and theresidue was purified by prep. LC (10-90% CH₃CN/H₂O modified with 0.1%TFA) to give the title compound as a white powder. MS (ESI, pos. ion.)m/z: 451 (M+1).

ADDITIONAL EXAMPLES

Following the procedure described above in Example 93, or with slightmodifications thereof, and following procedures familiar to one ofordinary skill in the art, the following examples were prepared fromcommercially available reagents:

MS (ESI, pos. ion) Example Structure m/z 94

451 (M + 1) 95

518 (M + 1) 96

440 (M + 1)

EXAMPLE 97

Dimethyl-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-aminetrifluoroacetate. A mixture of2-bromo-4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazole,(Example 86), (24 mg, 0.053 mmol) and dimethyl amine (2M in THF, 0.7 mL,1.4 mmol, Aldrich) was irradiated at 100° C. for 2 min in a microwavesynthesizer. The resulting mixture was evaporated under reduced pressureand the residue purified by prep. LC (20-100% CH₃CN/H₂O modified with0.1% TFA) to give the title compound as a white solid. MS (ESI, pos.ion.) m/z: 417 (M+1).

ADDITIONAL EXAMPLES

Following the procedure described above in Example 97, or with slightmodifications thereof, and following procedures familiar to one ofordinary skill in the art, the following examples were prepared fromcommercially available reagents:

MS (ESI, pos. ion) Example Structure m/z 98

458 (M + 1) 99

459 (M + 1) 100

486 (M + 1)

EXAMPLE 101

Pyridin-2-yl-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-aminetrifluoroacetate. A mixture of2-iodo-4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazole,(Example 91), (25 mg, 0.050 mmol), 2-aminopyridine (6 mg, 0.06 mmol,Aldrich), tris(dibenzylideneacetone)dipalladium(0) (5 mg, 0.005 mmol,Aldrich), sodium t-butoxide (7 mg, 0.07 mmol, Aldrich),2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (8 mg, 0.02 mmol,Acros) and dioxane/NMP (3/1, 1.5 mL) was heated at 200° C. for 10 min ina microwave synthesizer. The solvent was removed in vacuum and theresidue was purified by prep. LC (10-90% CH₃CN/H₂O modified with 0.1%TFA) to give the title compound as a white solid. MS (ESI, pos. ion.)m/z: 466 (M+1).

EXAMPLE 102

(a) 7-(6-Chloro-pyrimidin-4-yloxy)-quinoline. To a 100-mL,round-bottomed flask containing 4,6-dichloropyrimidine (5.1 g, 35 mmol,Aldrich), 7-hydroxyquinoline (5.0 g, 35 mmol, Aldrich), and DMF (30 mL)at room temperature was added potassium carbonate (4.8 g, 35 mmol,Aldrich). The suspension was stirred at 80° C. for 20 h under a N₂atmosphere. The reaction was diluted with H₂O (200 mL) and the solutionwas extracted with dichloromethane (2×200 mL). The combined extractswere dried over Na₂SO₄, filtered and concentrated under vacuum. Thecrude material was suspended in EtOAc, collected by filtration, andwashed with EtOAc to provide the title compound as a pale-brown solid.Mp: 151-152° C. MS (ESI, pos. ion.) m/z: 258 (M+1).

(b) 7-[6-(4-Chloro-phenyl)-pyrimidin-4-yloxy]-quinoline. To a 50-mL,round-bottomed flask containing 7-(6-chloro-pyrimidin-4-yloxy)-quinoline(1.5 g, 9.9 mmol) and ethylene glycol dimethyl ether (20 mL) was added4-chlorophenylboronic acid (1.7 g, 6.6 mmol, Lancaster) and 1 N sodiumcarbonate (20 mL). The solution was purged with N₂ at room temperaturefor 15 min and palladium(0)-tetrakis-triphenylphosphine (0.38 g, 0.33mmol, Strem Chemical) was added. The reaction mixture was heated at 100°C. for 16 h under a N₂ atmosphere and diluted at room temperature withwater (50 mL). The reaction mixture was extracted with EtOAc (2×100 mL),the organic phase was dried over sodium sulfate, and concentrated undervacuum. The crude material was purified by silica gel chromatography(gradient: 1-5% 2 N ammonia in methanol/dichloromethane) to obtain thetitle compound as a white solid. Mp: 184-185° C. MS (ESI, pos. ion.)mn/z: 334 (M+1).

ADDITIONAL EXAMPLES

Following the procedure described above for Example 102(b), or withslight modifications thereof, and following procedures familiar to oneof ordinary skill in the art, the following examples were prepared:

MS (ESI, pos. ion) Melting Example Structure m/z Point ° C. 103

318.1 (M + 1) 167.6-168.8 104

370.2 (M + 1) 186.2-188.1 105

350.1 (M + 1) 164.1-165.9 106

325.2 (M + 1) 232.6-234.2 107

367.5 (M + 1) 236.5-238  108

352.2 (M + 1) 240.6-242.8 109

330.2 (M + 1) 115.1 110

335.8 (M + 1) 194.4-196.2

EXAMPLE 111

7-[6-(4-Trifluoromethoxy-phenyl)-pyrimidin-4-yloxy]-quinoline. To a5-mL, microwave vial containing7-(6-chloro-pyrimidin-4-yloxy)-quinoline, (Example 102(a)), (0.30 g, 1.2mmol) and 1:1 toluene:EtOH (2.5 mL) was added4-trifluoromethoxyphenylboronic acid (0.30 g, 1.9 mmol, Aldrich), 2 Npotassium carbonate (2.5 mL), andpalladium(0)-tetrakis-triphenylphosphine (0.070 g, 0.060 mmol, StremChemical). The reaction mixture was heated at 1400C for 10 min in amicrowave synthesizer, allowed to cool to room temperature and dilutedwith water (5 mL) and 1 N sodium hydroxide (50 mL). The product wasextracted with dichloromethane (2×100 mL), dried over sodium sulfate,and concentrated in vacuum. The crude material was purified by silicagel chromatography (gradient: 1-1.7% 2 N ammonia inmethanol/dichloromethane) to obtain the title compound as a white solid.Mp: 67-168° C. MS (ESI, pos. ion.) m/z: 384 (M+1).

ADDITIONAL EXAMPLES

Following the procedure described above for Example 111, or with slightmodifications thereof, and following procedures familiar to one ofordinary skill in the art, the following examples were prepared:

MS (ESI, pos. ion) Melting Example Structure m/z Point ° C. 112

345 (M + 1) 243.9-245.8 113

384 (M + 1) 150.2-151.2 114

300 (M + 1) 150.0-150.5 115

383.3 (M + 1) oil 116

346.2 (M + 1) 137.9-138.3 117

335 (M + 1) 176.4-183.6 118

330.9 (M + 1) 172.2-178.0 119

435.8 (M + 1) 146.1-149.8 120

424.2 (M + 1) 170.2-171.6 121

332.2 (M + 1) 165.1-166.5 122

394 (M + 1) 207.7-208.4 123

353.1 (M + 1) 164-176

EXAMPLE 124

(a) 8-(6-Chloro-pyrimidin-4-yloxy)-quinolin-2-ylamine. To a 100-mL,round-bottomed flask containing 4,6-dichloropyrimidine (1.1 g, 7.5 mmol,Aldrich), 2-amino-8-hydroxyquinoline (0.60 g, 3.8 mmol, Sigma) and DMF(7 mL) at room temperature was added K₂CO₃ (0.52 g, 3.8 mmol, Aldrich).The suspension was stirred for 2 h under a N₂ atmosphere at 60° C. Thereaction mixture was treated with H₂O (50 mL) and the mixture wasextracted with dichloromethane (2×100 mL). The combined extracts weredried over Na₂SO₄, filtered, concentrated in vacuum and dried undervacuum for 16 h. The crude material was purified by silica gelchromatography (gradient: 1-3.5% 2 N ammonia inmethanol/dichloro-methane) to obtain the title compound. Mp: 185-186° C.MS (ESI, pos. ion.) m/z: 273 (M+1).

(b) 8-[6-Trifluoromethoxy-phenyl)-pyrimidin-4-yloxy]-quinolin-2-ylamine.To a 5-mL, microwave vial containing8-(6-chloro-pyrimidin-4-yloxy)-quinolin-2-ylamine (0.20 g, 0.73 mmol)and 1:1 toluene:EtOH (2.5 mL) was added 3-trifluoromethoxyphenylboronicacid (0.23 g, 1.5 mmol, Aldrich), 2 N potassium carbonate (2.5 mL), andpalladium(0)-tetrakis-triphenylphosphine (0.040 g, 0.040 mmol, StremChemical). The reaction mixture was heated at 140° C. for 10 min in amicrowave synthesizer, allowed to cool to room temperature and dilutedwith water (5 mL) and 1 N sodium hydroxide (50 mL). The mixture wasextracted with dichloromethane (2×100 mL), dried over Na₂SO₄, andconcentrated in vacuum. The crude material was purified by silica gelchromatography (gradient: 0-1.2% 2 N ammonia inmethanol/dichloromethane) to obtain the title compound as a white solid.Mp:148-150° C. MS (ESI, pos. ion.) m/z: 399 (M+1).

EXAMPLE 125

4-[6-(2-Amino-quinolin-8-yloxy)-pyrimidin-4-yl]-benzonitrile. Accordingto the procedure described for Example 124(b),8-(6-chloro-pyrimidin-4-yloxy)-quinolin-2-ylamine, (Example 124(a)),(0.20 g, 0.73 mmol) and 4-cyanophenylboronic acid (0.16 g, 1.1 mmol,Aldrich) provided the title compound as a white solid. Mp: 234-2360C. MS(ESI, pos. ion.) nzlz:340 (M+1).

EXAMPLE 126

7-[6-(3-Pyrrolidin-1-yl-phenyl)-pyrimidin-4-yloxy]-quinoline. Accordingto the procedure described for Example 124(b), from7-(6-chloro-pyrimidin-4-yloxy)-quinoline, (Example 102(a)), (0.070 g,0.25 mmol) and 3-pyrrolidinephenyl-boronic acid (0.070 g, 0.38 mmol,Asymchem) was obtained the title compound as a pale yellow oil. MS (ESI,pos. ion.) m/z:369 (M+1).

EXAMPLE 127

(a) 7-(6-Benzoftiran-5-yl-pyrirnidin-4-yloxy)-quinoline. To a 25-mL,pressure vial containing 7-(6-chloro-pyrimidin-4-yloxy)-quinoline,(Example 102(a)), (0.20 g, 0.78 mmol) and ethylene glycol dimethyl ether(3 mL) was added benzofuran-5-boronic acid (0.14 g, 1.2 mmol, preparedaccording to Goodby, J. W.; Toyne, K. J.; Hird, M.; Friedman, M. R.;Jones, John C. PCT Int. Appl. WO 0121606, 2001), 1 N sodium carbonate(2.3 mL), palladium acetate (0.010 g, 0.040 mmol, Aldrich), andtri-o-tolyl-phosphine (0.030 g, 0.090 mmol, Aldrich). The reactionmixture was purged with N₂ at room temperature for 15 min then thereaction flask was sealed and heated at 800C for 16 h. After cooling,the reaction mixture was diluted with water (5 mL) and 1 N sodiumhydroxide (50 mL). The product was extracted with dichloromethane (2×100mL), dried over Na₂SO₄, filtered and concentrated in vacuum. The crudematerial was purified by silica gel chromatography (gradient: 0-2% 2 Nammonia in methanol/dichloromethane) to obtain the title compound as anoff-white solid. Mp: 234-237° C. MS (ESI, pos. ion.) m/z: 340 (M+1).

EXAMPLE 128

(a) 7-(6-Iodo-pyrimidin-4-yloxy)-quinoline. To a round-bottomed flaskcontaining 7-(6-chloro-pyrimidin-4-yloxy)-quinoline, (Example 102(a)),(0.20 g, 0.80 mmol) and sodium iodide (0.20 g, 1.2 mmol, Aldrich) wasadded hydriodic acid (2.5 mL, Aldrich). The reaction mixture was stirredat 40° C. for 2 h, treated with 1 N sodium hydroxide and extracted withdichloromethane (2×40 mL). The combined organic layers were dried overNa₂SO₄ and concentrated in vacuum. The crude material was purified bysilica gel chromatography (gradient: 2-2.5% 2 N ammonia inmethanol/dichloromethane) to obtain the title compound as a yellowsolid.

(b) 7-[6-(4-Bromo-phenyl)-pyrimidin-4-yloxy]-quinoline. To a 5 mL,round-bottomed flask containing 7-(6-iodo-pyrimidin-4-yloxy)-quinoline(0.16 g, 0.45 mmol) and ethylene glycol dimethyl ether (2 mL) was added4-bromophenylboronic acid (0.14 g, 0.68 mmol, Aldrich) and 1 N sodiumcarbonate (1.4 mL). The reaction mixture was purged with N₂ at roomtemperature for 15 min and palladium(0)-tetrakis-triphenylphosphine(0.030 g, 0.020 mmol, Strem Chemical) was added. The reaction mixturewas heated at 100° C. for 1.5 h under a N₂ atmosphere, then treated atroom temperature with water (50 mL). The mixture was extracted withEtOAc (2 x 100 mL) and the combined organic layers were dried overNa₂SO₄ and concentrated in vacuum. The crude material was purified bysilica gel chromatography (gradient: 1-2% 2 N ammonia inmethanol/dichloromethane) to obtain the title compound as a white solid.Mp: 160-162° C. MS (ESI, pos. ion.) m/z: 378 (M+1).

EXAMPLE 129

(a) 4,6-Diiodo-pyrimidine. A mixture of 4,6-dichloro-pyrimidine (1.0 g,6.7 mmol, Aldrich), NaI (1.4 g, 9.0 mmol), and hydriodic acid (20 mL,0.15 mol) was heated at 40° C. for 1 h and stirred at room temperaturefor additional 20 h. The reaction mixture was basified with 10 N NaOH topH 10. The resulting precipitate was collected by filtration, washedwith water, and dried in vacuum to give the title compound as alight-yellow solid. MS (ESI, pos.ion) m/z: 332 (M+2).

(b) 4-(6-Iodo-pyrimidin-4-yloxy)-benzothiazol-2-ylamine. A mixture of4,6-diiodo-pyrimidine (720 mg, 2.2 mmol), 2-amino-benzothiazol-4-ol (360mg, 2.2 mmol, CarboGen), and K₂CO₃ (430 mg, 3.1 mmol) in DMSO (3.0 mL)was heated at 80° C. for 1 h. The reaction mixture was allowed to coolto room temperature, treated with water and stirred for 18 h. Theresulting precipitate was collected by filtration, washed with water,and dried in vacuum to give the title compound as a light-yellow solid.MS (ESI, pos. ion) m/z: 371 (M+1).

(c) 4-[6-(4-Bromo-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine. Toa 5-mL, microwave vial containing4-(6-iodo-pyrimidin-4-yloxy)-benzothiazol-2-ylamine (0.30 g, 0.81 mmol)and 1:1 toluene:EtOH (2 mL) was added 4-bromophenylboronic acid (0.23 g,1.5 mmol, Aldrich), 2 N potassium carbonate (1.2 mL), andpalladium(0)-tetrakis-triphenylphosphine (0.050 g, 0.040 mmol, StremChemical). The reaction mixture was heated at 1400C for 10 min in amicrowave synthesizer, allowed to cool to room temperature and dilutedwith water (5 mL) and 1 N sodium hydroxide (50 mL). The mixture wasextracted with EtOAc (2×100 mL) and the combined organic layers weredried over Na₂SO₄, and concentrated in vacuum. The crude material waspurified by silica gel chromatography (gradient: 0-65% EtOAc/Hexanes) toobtain the title compound. Mp: 228-229° C. MS (ESI, pos. ion.) m/z: 401(M+1).

EXAMPLE 130

N-{4-[6-(4-Bromo-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide.To a 50 mL, round-bottomed flask containing4-[6-(4-bromo-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine,(Example 129(c)), (0.050 g, 0.13 mmol) was added anhydrous toluene (3mL) and acetic anhydride (0.010 mL, 0.39 mmol, Aldrich). The mixture washeated at 90° C. and the progress of the reaction was monitored by TLC(developed in 50% EtOAc/hexanes). After reaching completion, thereaction mixture was allowed to cool to room temperature, the whiteprecipitate was collected by filtration, washed with MeOH (5 mL), anddried under vacuum to obtain the title compound as a white solid. Mp:271-272° C. MS (ESI, pos. ion.) m/z: 441 (M+1).

EXAMPLE 131

2-[6-(Quinolin-7-yloxy)-pyrimidin-4-yl]-phenol. To a 50-mL,round-bottomed flask containing7-[6-(2-methoxy-phenyl)-pyrimidin-4-yloxy]-quinoline, (Example 109),(0.09 g, 0.27 mmol) was added dichloromethane (3 mL). The solution wascooled to −78° C. and BBr₃ (0.82 mL, 0.82 mmol, 1 N in dichloromethane,Aldrich) was added. The reaction mixture was allowed to warm to roomtemperature over 1 h and then cooled to −78° C. and quenched with satdsodium bicarbonate (10 mL). The reaction mixture was diluted with water(50 mL) and extracted with dichloromethane (2×100 mL). The combinedorganic layers were dried over Na₂SO₄ and concentrated in vacuum. Theresulting solid was suspended in methanol (15 mL) and the remainingsolid was collected by filtration, and dried under vacuum to obtain thetitle compound as a white solid. Mp: 188-191° C. MS (ESI, pos. ion.)m/z: 316 (M+1).

EXAMPLE 132

7-(6-Pyridin-3-yl-pyrimidin-4-yloxy)-quinoline. To a 5 mL, microwavevial containing 7-(6-chloro-pyrimidin-4-yloxy)-quinoline, (Example102(a)), (0.30 g, 1.2 mmol) and ethylene glycol dimethyl ether (2 mL)was added 3-diethyl (3-pyridyl)borane (0.21 g, 1.5 mmol, Aldrich), 1 Nsodium carbonate (1.8 mL), and palladium(0)-tetrakis-triphenylphosphine(0.14 g, 0.15 mmol, Strem Chemical). The vial was sealed and heated at200° C. for 20 min in a microwave synthesizer, allowed to cool to roomtemperature, and the reaction mixture was diluted with 1 N sodiumhydroxide (25 mL) and extracted with dichloromethane (2×50 mL). Theorganic layers were combined, dried over Na₂SO₄, filtered andconcentrated onto silica gel. The crude material was purified by silicagel chromatography (gradient: 1-2% 2 N ammonia inmethanol/dichloromethane) to obtain the title compound as an off-whitesolid. Mp: 155-158° C. MS (ESI, pos. ion.) mn/z: 301 (M+1).

EXAMPLE 133

(a) 4-(6-Chloro-pyrimidin-4-yloxy)-benzothiazol-2-ylamine. To a 100-mL,round-bottomed flask containing 4,6-dichloro-pyrimidine (9.0 g, 60 mmol,Aldrich) and 2-amino-benzothiazol-4-ol (5.0 g, 30 mmol, CarboGen) wasadded potassium carbonate (4.1 g, 30 mmol, Aldrich) anddimethylsulfoxide (10 mL). The reaction mixture was heated at 95° C.with stirring for 4.5 h, and at room temperature for 16 h. The resultingsolid was collected by filtration, washed with water (500 mL) anddichloromethane (500 mL), and dried under vacuum to obtain the titlecompound as a yellow solid.

(b)4-[6-(2,2-Dimethyl-2,3-dihydro-benzofuran-6-yl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine.A 50-mL, round-bottomed flask containing2,3-dihydro-2,2-dimethylbenzofuran-6-boronic acid (1.0 g, 5.4 mmol,ChemShop), 4-(6-chloro-pyrimidin-4-yloxy)-benzothiazol-2-ylamine (1.0 g,3.6 mmol), and ethylene glycol dimethyl ether (6 mL) was degassed withN₂ for 15 min. 2 N Potassium carbonate (5.4 mL) andpalladium(0)-tetrakis-triphenylphosphine (0.62 g, 0.54 mmol, StremChemical) were added and the reaction mixture was heated at 90° C. for16 h, then allowed to come to room temperature, diluted with water (200mL), and extracted with dichloromethane (2×200 mL). The dichloromethanelayers were dried over Na₂SO₄, filtered and concentrated under vacuum.The orange solid was suspended in methanol (50 mL), collected byfiltration, and then washed with methanol (50 mL) and dichloromethane(50 mL) to obtain the title compound. Mp: 247-248° C. MS (ESI, pos.ion.) m/z: 391 (M+1).

EXAMPLE 134

N-{4-[6-(2,2-Dimethyl-2,3-dihydro-benzofuran-6-yl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide.To a 100-mL, round-bottomed flask containing4-[6-(2,2-dimethyl-2,3-dihydro-benzofuran-6-yl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine,(Example 133(b)), (0.50 g, 1.3 mmol) was added toluene (7 mL) and aceticanhydride (0.40 mL, 3.8 mmol, Aldrich). The reaction mixture was heatedat 85° C. for 2 h. The toluene was removed in vacuum and the resultingorange solid was re-dissolved in dichloromethane (125 mL), washed withwater (150 mL), dried over Na₂SO₄ and concentrated in vacuum. Theresulting orange solid was suspended in dichloromethane (100 mL),collected by filtration, and dried under vacuum to obtain the titlecompound as a white solid. Mp: 224-225° C. MS (ESI, pos. ion.) m/z: 433(M+1).

EXAMPLE 135

(a) 1-Methoxymethoxy-3-trifluoromethyl-benzene. Chloromethyl methylether (1.5 mL, 20 mmol, Aldrich) was added dropwise to a 50-mL,round-bottomed flask containing a solution of α, α, α-trifluoro-m-cresol(2.0 mL, 16 mmol, Aldrich), and N,N-diisopropylethyl-amine (5.7 mL, 33mmol, Aldrich) in dichloromethane (6 mL) at 0° C. The reaction mixturewas allowed to come to room temperature and stirred for 3 h after whichthe solvents were removed under vacuum. EtOAc (10 mL) was then added tothe reaction flask and the resulting white solid was removed byfiltration. The filtrate was concentrated onto silica gel and the crudematerial was purified by silica gel chromatography (gradient: 2.4-10%EtOAc/hexanes) to obtain the title compound as a clear, colorless oil.

(b) 2-Methoxymethoxy-6-trifluoromethylphenylboronic acid.sec-Butyllithium (220 mL, 290 mmol, 1.35 N in hexanes, Aldrich) wasadded dropwise to a solution of N,N, N′,N′-tetramethylethylenediamine(45 mL, 0.29 mmol, Aldrich) in anhydrous ether (250 mL) with stirring at−400C under argon. After sirring at −400C for 15 min, a solution of1-methoxymethoxy-3-trifluoromethyl-benzene (100 mL, 2.4 N in anhydrousether) was added dropwise and the reaction mixture was stirred at roomtemperature for 2 h. Trimethyl borate (82 mL, 0.72 mL, Aldrich) wasadded slowly at −78° C. and the reaction mixture was stirred at roomtemperature for 16 h. Ice water (100 mL) was added to the reactionmixture, which after stirring for 10 min was transferred to a 2-L,Morton flask and stirred vigorously with 1 N sodium hydroxide (1 L) for1 h. The organic and aqueous layers were separated and the aqueous layerwas washed with ether (500 mL). The aqueous layer was cooled in an icebath and treated with glacial acetic acid until it reached pH 5. Thewhite precipitate was collected by filtration and washed with water (1L), hexanes (1 L), and dried under vacuum to obtain the title compoundas an off-white solid.

(c)4-[6-(2-Methoxymethoxy-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine.2 N Potassium carbonate (11 mL, 22 mmol) was added to a round-bottomedflask containing 2-methoxymethoxy-4-trifluoromethyl-phenylboronic acid(3.6 g, 14 mmol),4-(6-chloro-pyrimidin-4-yloxy)-benzo-thiazol-2-ylamine, (Example 133(a),(2.0 g, 7.2 mmol), and ethylene glycol dimethyl ether (13 mL). Themixture was then purged with N₂ for 15 min andpalladium(0)-tetrakis-triphenylphosphine (0.42 g, 0.36 mmol, StremChemical) was added. The reaction mixture was heated at 80° C. for 16 h,allowed to cool to room temperature, diluted with water (300 mL) andextracted with dichloro-methane (2×200 mL). The combined dichloromethanelayers were washed with brine (200 mL), dried over Na₂SO₄, andconcentrated under vacuum. The resulting white solid was suspended inMeOH (50 mL) and collected by filtration to obtain the title compound asa white solid. Mp: 175-176° C. MS (ESI, pos. ion.) m/z: 449 (M+1).

EXAMPLE 136

(a) N-[4-(6-Chloro-pyrimidin-4-yloxy)-benzothiazol-2-yl]-acetamide. To around-bottomed flask containing4-(6-chloro-pyrimidin-4-yloxy)-benzothiazol-2-ylamine, (Example 133(a))(4.0 g, 14 mmol) was added toluene (10 mL) and acetic anhydride (4.1 mL,43 mmol, Aldrich). The reaction mixture was heated at 85° C. for 2 h andthen stirred at room temperature for 16 h. The solvent was removed undervacuum and the resulting orange solid was suspended in dichloromethane,collected by filtration and dried under vacuum to obtain the titlecompound as an off-white solid. Mp: 268-275° C. MS (ESI, pos. ion.) m/z:321 (M+1)<

(b)N-{4-[6-(2-Methoxymethoxy-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide.2 N Potassium carbonate (19 mL, 38 mmol) was added to a round-bottomedflask containing 2-methoxymethoxy-4-trifluoro-methylphenylboronic acid,(Example 135(b)), (6.2 g, 25 mmol),N-[4-(6-chloro-pyrimidin-4-yloxy)-benzothiazol-2-yl]-acetamide (4.0 g,13 mmol), and ethylene glycol dimethyl ether (25 mL). The mixture wasthen purged with nitrogen for 15 min, andpalladium(0)-tetrakis-triphenylphosphine (0.73 g, 0.63 mmol, StremChemical) was added. The reaction mixture was heated at 80° C. for 16 h,diluted with water (300 mL) and extracted with dichloromethane (2×200mL). The combined organic extracts were washed with brine (200 mL),dried over Na₂SO₄, and concentrated in vacuum. The resulting white solidwas suspended in MeOH (50 mL) and collected by filtration to obtain thetitle compound as an off-white solid. Mp: 223.0-225.3° C. MS (ESI, pos.ion.) mn/z: 492 (M+1).

EXAMPLE 137

N-{4-[6-(2-Hydroxy-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide.Trifluoroacetic acid (0.10 mL, 1.3 mmol, Aldrich) was added dropwise toa solution of N-{4-[6-(2-methoxymethoxy-4-trifluoromethyl-phenyl)-15pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide, (Example 136(b)), (0.50g, 1.0 mmol) in dichloromethane (10 mL) with stirring and cooling in anice bath. The reaction mixture was stirred for 16 h at room temperature,diluted with dichloromethane (5 mL) and quenched with satd sodiumbicarbonate solution. The reaction mixture was diluted with water (100mL), extracted with dichloro-methane (2×100 mL), and the combinedorganic extracts were concentrated in vacuum. The resulting white solidwas suspended in MeOH (50 mL), collected by filtration, and dried undervacuum to obtain the title compound as a white solid. Mp: 302-304° C. MS(ESI, pos. ion.) m/z: 445 (M+1).

EXAMPLE 138

2-[6-(2-Amino-benzothiazol-4-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenol.To a 100-mL, round-bottomed flask containing a solution of4-[6-(2-methoxy-methoxy-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine,(Example 135(c)), (1.8 g, 3.9 mmol) in dichloromethane (39 mL) was addedboron trifluoride diethyl etherate (1.5 mL, 12 mmol, Aldrich) withstirring at −78° C. The reaction mixture was then stirred at 0° C. for 1h and at room temperature for 3 h. The mixture was quenched with satdsodium bicarbonate at 0° C. and extracted with dichloromethane (2×100mL). The combined organic extracts were dried over Na₂SO₄, filtered andconcentrated in vacuum. The crude material was purified by silica gelchromatography (gradient: 0-3% 2 N ammonia in methanol/dichloromethane)to yield the title compound as an amorphous, white solid. MS (ESI, pos.ion.) m/z: 406 (M+1).

EXAMPLE 139

N-{4-[6-(2-Benzyloxy-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide.To a mixture ofN-{4-[6-(2-hydroxy-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide,(Example 137), (0.20 g, 0.50 mmol) and potassium carbonate (0.062 g,0.45 mmol, Aldrich) in anhydrous acetone (2 mL) was added benzyl bromide(0.053 mL, 0.45 mmol, Aldrich) and the reaction mixture was heated at70° C. for 2 h. The solvent was removed under vacuum and the residue wasdiluted with water (50 mL) and extracted with ether (2×100 mL). Thecombined organic extracts were washed with water (100 mL), dried overNa₂SO₄, filtered and concentrated under vacuum. The crude material waspurified by silica gel chromatography (gradient: 5-60% EtOAc/hexanes) toobtain the title compound (0.030 g, 13%) as a white solid. Mp: 201-203°C. MS (ESI, pos. ion.) m/z: 537 (M+1).

EXAMPLE 140

Trifluoro-methanesulfonic acid2-[6-(2-acetylamino-benzothiazol-4-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenylester. To a solution ofN-{4-[6-(2-hydroxy-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide,(Example 137), (1.5 g, 3.4 mmol) and N-phenyltrifluoromethanesulfonimide (1.5 g, 4.0 mmol, Aldrich) in dichloromethane (10 mL) andDMF (10 mL) was added N,N-diisopropylethylamine (2.4 mL, 14 mmol,Aldrich) and the reaction mixture was stirred at room temperature for 20h. Water (50 mL) was added and the mixture was extracted withdichloromethane (2×150 mL). The combined organic extracts were washedwith water (100 mL), dried over Na₂SO₄, filtered and concentrated undervacuum. The white solid was suspended in methanol (50 mL), collected byfiltration, and dried under vacuum to obtain the title compound as awhite solid. Mp: 209-212° C. MS (ESI, pos. ion.) m/z: 580 (M+1).

EXAMPLE 141

N-{4-[6-(4-Trifluoromethyl-2-vinyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide.Trifluoromethanesulfonic acid2-[6-(2-acetylamino-benzothiazol-4-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenylester, (Example 140), (1.0 g, 1.7 mmol) was dissolved in dioxane (7.7mL) in a 100-mL, round-bottomed flask. Tributylvinylstannane (0.60 mL,1.9 mmol, Fluka), lithium chloride (0.22 g, 5.1 mmol, Aldrich),palladium(0)-tetrakis-triphenylphosphine (0.040 g, 0.030 mmol, StremChemical), and a few crystals 2,6-di-tert-butyl-4-methylphenol (Aldrich)were added to the solution. The reaction was heated at 98° C. for 5 hafter which the solvent was removed under vacuum and the crude materialwas purified by silica gel chromatography (gradient: 0-10%methanol/dichloromethane) to obtain the title compound as a yellowsolid. Mp: 234-237 C. MS (ESI, pos. ion.) m/z: 458 (M+1).

EXAMPLE 142

2-[6-(2-Acetylamino-benzothiazol-4-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-benzoicacid methyl ester. Ozone was passed through a solution ofN-{4-[6-(4-trifluoromethyl-2-vinyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide,(Example 141), (0.050 g, 0.11 mmol) in dichloromethane (1 mL) and sodiumhyroxide (0.22 mL, 2.5 N in methanol) at −78° C. Once the solutionshowed a noticeable blue color and a yellow precipitate was observed,the reaction mixture was purged with oxygen and diluted with water (50mL). The product was extracted with ether (2 x 50 mL). The combinedether layers were dried over Na₂SO₄, filtered and concentrated undervacuum. The crude material was purified by silica gel chromatography(gradient: 0-60% EtOAc/hexanes) yielding the title compound as anamorphous white solid. MS (ESI, pos. ion.) m/z: 489 (M+1).

EXAMPLE 143

(a) 1-(6-Amino-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone. To asolution of 1-(3,3-dimethyl-6-nitro-2,3-dihydroindol-yl)ethanone (110mg, 0.47 mmol, prepared according to WO 03/049702 A2) in ethyl ether (3mL), magnetically stirred in a round-bottomed flask at 0° C., was addedtin (II) chloride dihydrate (0.67 g, 2.96 mmol, Aldrich) and cond HCl(0.3 mL). The reaction mixture was stirred at 0° C. for 10 min, allowedto warm to 25° C. then stirred at that temperature for 18 h. Thereaction mixture was washed with 10 N NaOH (10 mL), extracted with EtOAcand concentrated in vacuum to give the title compound, which was used inthe next step without additional purification.

(b) 1-(6-Iodo-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone. To amixture of 1-(6-amino-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone (2.2g, 10 mmol), copper iodide (1.9 g, 10 mmol, Aldrich), iodine (1.3 g, 5mmol, Aldrich) and potassium iodide (1.7 g, 10 mmol, Aldrich) in DME (60mL) was added isoamyl nitrite (4 mL, 30 mmol, Aldrich). The reaction washeated at 65° C. for 1 h and the insoluble material was filtered througha pad of Celite®, and washed with EtOAc. The filtrate was washed withaqueous ammonium hydroxide, aqueous sodium bisulfite and brine. Theorganic layer was dried over Na₂SO₄, filtered, evaporated under vacuumand the residue purified by silica gel chromatography (1:4 ofEtOAc/hexanes) to give the title compound as a light-yellow solid. MS(ESI, pos. 15 ion) m/z: 316 (M+1).

(c)1-[3,3-Dimethyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-indol-1-yl]-ethanone.To 1-(6-iodo-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone (63 mg, 0.2mmol) dissolved in DMSO (0.5 mL) was added bis(pinacolato)diboron (56mg, 0.22 mmol, Aldrich), potassium acetate (59 mg, 0.6 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (10 mg, 0.07 mmol %, Aldrich). Nitrogen was bubbledthrough the reaction for 5 min. The reaction mixture was then heated ina microwave synthesizer at 220° C. for 10 min, allowed to cool to roomtemperature and partitioned between EtOAc and brine. The aqueous layerwas separated, extracted with EtOAc and the combined organic extractswere dried over Na₂SO₄, filtered and concentrated under vacuum.Purification of the residue by silica gel chromatography (1:2.5 ofEtOAc/hexanes) provided the title compound. MS (ESI, pos. ion) m/z: 316(M+1).

(d) 1-Acetyl-2,3-dihydro-3,3-dimethylindol-6-ylboronic acid. To asolution of1-[3,3-dimethyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-indol-1-yl]-ethanone(0.14 g, 0.44 mmol) in a mixture of THF (4 mL) and water (1 mL) wasadded sodium periodate (0.28 g, 1.3 mmol, Aldrich) and the mixture wasstirred at 25° C. for 5 min. 2 N HCl was then added dropwise and thereaction mixture was stirred at 25° C. for 16 h. The mixture waspartitioned between EtOAc and brine, the aqueous layer was separated andextracted with EtOAc. The combined organic extracts were dried overNa₂SO₄, filtered and concentrated under vacuum. Purification of theresidue by silica gel chromatography (5:1 of EtOAc/hexanes) provided thetitle compound as a tan solid. MS (ESI, pos. ion) m/z: 234 (M+1).

(e)1-{3,3-Dimethyl-6-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-2,3-dihydro-indol-1-yl}-ethanonetrifluoroacetate. To a solution of1-acetyl-2,3-dihydro-3,3-dimethylindol-6-ylboronic acid (40 mg, 0.17mmol) and 7-(6-chloro-pyrimidin-4-yloxy)-quinoline, (Example 102(a)),(50 mg, 0.19 mmol) in DME (0.5 mL) was added Pd(PPh₃)₄ (20 mg, 0.017mmol, Strem Chemical) and aqueous Na₂CO₃. The reaction mixture washeated at 80° C. for 16 h, allowed to cool to room temperature andpartitioned between EtOAc and brine. The aqueous layer was separated,extracted with EtOAc and the combined organic extracts were dried overNa₂SO₄, filtered and concentrated in vacuum. Purification of the residueby silica gel chromatography (5:1 of EtOAc/hexanes), followed bypreparative HPLC separation afforded the title compound as a white foam.MS (ESI, pos. ion) m/z: 411 (M+1).

EXAMPLE 144

(a) 5-Chloro-2-fluoro-4-(4-trifluoromethyl-phenyl)-pyridine. The titlecompound was prepared analogous to Example 1 using5-chloro-2-fluoro-4-iodopyridine (0.64 g, 2.5 mmol, AsymChem),4-(trifluoromethyl)benzeneboronic acid (0.52 g, 2.8 mmol, Aldrich),tetrakis(triphenylphosphine)palladium(0) (0.29 g, 0.25 mmol, StremChemical) and aq sodium carbonate (0.29 g in 10 mL of water) in toluene(10 mL). Purification by silica gel chromatography (1:9 ofEtOAc/hexanes) provided the title compound as a white solid. MS m/z: 276(M+1).

(b) Acetic acid 2-acetylamino-benzothiazol-4-yl ester. To the suspensionof 2-amino-4-hydroxybenzothiazole (8.3 g, 50 mmol, Fluorochem Ltd.) intoluene (100 mL) was added acetic anhydride (47 mL, 500 mmol). Thereaction mixture was heated at 110° C. for 16 h. The solvents wereevaporated to give the title compound as a tan solid. MS m/z: 251 (M+1).

(c) N-(4-Hydroxy-benzothiazol-2-yl)-acetamide. To the suspension ofacetic acid 2-acetylamino-benzothiazol-4-yl ester (9.7 g, 39 mmol) inMeOH (200 mL) was added potassium carbonate (11 g, 78 mmol). Thereaction mixture was stirred at 25° C. for 6 h, most of the solvent wasevaporated uinder vacuum and the residue was acidified with 10% HCl topH 5. The mixture was then extracted with EtOAc (3 x), the combinedEtOAc extracts were washed with brine, dried over Na₂SO₄ filtered andconcentrated in vacuum to give the title compound as a tan solid. MSm/z: 209 (M+1).

(d)N-{4-[5-Chloro-4-(4-trifluoromethyl-phenyl)-pyridin-2-yloxy]-benzothiazol-2-yl}-acetamide.To N-(4-hydroxy-benzothiazol-2-yl)-acetamide (0.13 g, 0.6 mmol)dissolved in DMSO (2 mL) was added NaH (29 mg, 0.72 mmol). Afterstirring at 25° C. for 10 min,5-chloro-2-fluoro-4-(4-trifluoromethyl-phenyl)-pyridine, (Example144(a)), (0.11 g, 0.4 mmol) and copper iodide (8 mg, 0.04 mmol) wereadded. The reaction mixture was heated at 90° C. for 20 h, allowed tocool to room temperature and partitioned between EtOAc and brine. Theaqueous layer was separated, extracted with EtOAc, and the combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated invacuum. Purification of the residue by silica gel chromatography (1:2.5of EtOAc/hexanes) gave the title compound as a white solid. MS (ESI,pos. ion) nzlz: 411 (M+1). Mp: 240.2-240.3° C.

EXAMPLE 145

(a) 5-Bromo-2-chloro-4-iodopyridine. n-Butyllithium (16.3 mL, 26 mmol,1.6 M in hexane, Aldrich) was added dropwise to a solution ofdiisopropylamine (3.6 mL, 26 mmol, Aldrich) in THF (15 mL) with stirringat −78° C. After the addition was complete, the reaction mixture wasstirred at −78° C. for 30 min. Then, 5-bromo-2-chloropyridine (5 g, 26mmol, Lancaster) dissolved in THF (15 mL) was introduced dropwise andthe reaction was stirred at −78° C. for another 5 h. A solution ofiodine (8 g, 31.5 mmol) in 15 mL of THF was added slowly and thereaction was stirred at −78° C. for 2 h. THF and water (1:1, 100 mL) wasadded to quench the reaction. The mixture was allowed to warm to roomtemperature and 1 M sodium bisulfite (50 mL) was added. The resultingmixture was stirred at room temperature for 1 h, extracted with EtOAcand washed with water. The aqueous layer was extracted with EtOAc andthe combined organic extracts were dried over Na₂SO₄, filtered andevaporated under vacuum. Recrystallization of the residue fromEtOAc/hexanes provided the title compound as a brown solid.

(b) 5-Bromo-2-chloro-4-(4-trifluoromethyl-phenyl)-pyridine. The titlecompound was prepared analogous to Example 1 using5-bromo-2-chloro-4-iodopyridine (0.1 g, 0.3 mmol),4-(trifluoromethyl)benzeneboronic acid (68 mg, 0.36 mmol, Aldrich),tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol, Aldrich) andaqueous sodium carbonate (38 mg in 0.3 mL of water) in toluene (1 mL).Purification by silica gel chromatography (1:9 of EtOAc/hexanes)provided the title compound as a white solid. MS (ESI, pos. ion) m/z:337, 339 (M+1).

(c)N-{4-[5-Bromo-4-(4-trifluoromethyl-phenyl)-pyridin-2-yloxy]-benzothiazol-2-yl}-acetamide.The title compound was prepared analogous to Example 144(d) usingN-(4-hydroxy-benzothiazol-2-yl)-acetamide, (Example 144(c)), (94 mg,0.45 mmol), 5-bromo-2-chloro-4-(4-trifluoromethyl-phenyl)-pyridine (84mg, 0.25 mmol), and NaH (16 mg, 0.4 mmol, Aldrich) in DMF (0.5 mL) byheating at 150° C. for 6 h. Purification by silica gel chromatography(1:3 of EtOAc/hexanes) gave the title compound as a white solid. MS(ESI, pos. ion) m/z: 509, 511 (M+1). Mp: 245.7-245.8° C.

EXAMPLE 146

N-{4-[5-(4-Fluoro-phenyl)-4-(4-trifluoromethyl-phenyl)-pyridin-2-yloxy]-benzothiazol-2-yl}-acetamide.To a mixture ofN-{4-[5-bromo-4-(4-trifluoromethyl-phenyl)-pyridin-2-yloxy]-benzothiazol-2-yl}-acetamide,(Example 145(b)), (51 mg, 0.1 mmol) and 4-fluorophenylboronic acid (18mg, 0.13 mmol, Aldrich) in dioxane (1 mL) was added Pd(PPh₃)₄ (6 mg,0.005 mmol, Aldrich) and aqueous Na₂CO₃ (16 mg in 0.2 mL of water). Thereaction mixture was heated in microwave synthesizer at 1600C for 30min. Purification by silica gel chromatography (EtOAc/hexanes) gave thetitle compound as a white solid. MS (ESI, pos. ion) m/z: 524 (M+1). Mp:112.3-130.1° C.

EXAMPLE 147

N-{4-[5-(4-Trifluoromethoxy-phenyl)-4-(4-trifluoromethyl-phenyl)-pyridin-2-yloxy]-benzothiazol-2-yl}-acetamidetrifluoroacetate. This material was prepared analogous to Example 146 byusingN-{4-[5-bromo-4-(4-trifluoromethyl-phenyl)-pyridin-2-yloxy]-benzothiazol-2-yl}-acetamide,(Example 145(b)), (0.1 g, 0.2 mmol), 4-(trifluoromethoxy)phenyl boronicacid (53 mg, 0.26 mmol, Aldrich), Pd(PPh₃)₄ (23 mg, 0.02 mmol, Aldrich)and aq. Na₂CO₃ (32 mg in 0.4 mL of water) in dioxane (2 mL).Purification by silica gel chromatography (1:2 of EtOAc/hexanes),followed by preparative HPLC separation gave the title compound as awhite solid. MS (ESI, pos. ion) n7mz: 590 (M+1). Mp: 212.9-222.3° C.

EXAMPLE 148

(a) (3-Trifluoromethylphenyl)carbamic acid tert-butyl ester. To a250-mL, round-bottomed flask was added 3-(trifluoromethyl)aniline (5.0g, 31 mmol, Aldrich), THF (100 mL), di-tert-butyl dicarbonate (20. g, 93mmol, Aldrich) and 4-(dimethylamino)pyridine (0.38 g, 3.1 mmol,Aldrich). The mixture was heated at reflux for 3 h. K₂CO₃ (13 g, 93mmol) and MeOH (50 mL) were added, and heating was continued for 18 h.After cooling to room temperature, the mixture was diluted with CH₂Cl₂,then filtered and washed with CH₂Cl₂ The filtrate was concentrated toafford a brown oil. The oil was dissolved in EtOAc (200 mL) and washedwith H₂O (2×100 mL), brine (1×100 mL), dried over Na₂SO₄, filtered andconcentrated in vacuum onto silica gel. Purification by silica gelchromatography with gradient from 0% to 15% solution of EtOAc in hexanesafforded the title compound as a colorless oil which solidified uponstanding to a while solid. MS (ESI, neg. ion.) m/z: 260 (M−1).

(b) [2-(6-Chloropyrimidin-4-yl)-5-trifluoromethylphenyl]carbamic acidtert-butyl ester. (Analogous to the procedures of Boisnard, S.;Carbonnelle, A. C.; Zhu, J. Org Let. 2001, 3, 2061-2064 and Hewawasam,P.; Meanwell, N. A. Tetrahedron Lett. 1994, 35, 7303). To a 500-mL,round-bottomed flask containing (3-trifluoromethylphenyl)carbamic acidtert-butyl ester (2.5 g, 9.6 mmol) in THF (100 mL) stirred at −40° C.was added sec-BuLi (17 mL, 1.3 M in cyclohexane, Aldrich) over 10 min.The mixture was stirred for 1 h at −40° C. and then cooled to −78° C.Trimethyl borate (4.4 mL, 38 mmol, Aldrich) was added over 10 min. Thereaction mixture was allowed to warm to room temperature and stirred for10 min at that temperature. The mixture was quenched with aq KH₂PO₄ andconcentrated to remove the THF. The aqueous mixture was then extractedwith EtOAc (3×100 mL) and the combined extracts were washed with brine,dried over Na₂SO₄, filtered, and concentrated to afford a yellow foam.The foam was dissolved in CH3CN (30 mL) and treated with4,6-dichloropyrimidine (4.1 g, 28 mmol, Aldrich) followed by a solutionof Na₂CO₃ (2.9 g, 28 mmol) in H₂O (30 mL).Tetrakis(triphenylphosphine)palladium(0) (0.53 g, 0.46 mmol, Strem) wasthen added and the mixture was stirred at 75° C. for 15 h. Afterallowing to cool to room temperature, the mixture was concentrated invacuum to remove the CH₃CN and then extracted with EtOAc. The combinedextracts were washed with H₂O and brine, dried over Na₂SO₄ andconcentrated in vacuum. Purification of the residue by silica gelchromatography with gradient from 0% to 10% solution of EtOAc in hexanesafforded the title compound as a colorless oil. MS (ESI, pos. ion.) m/z:374 (M+1).

(c){2-[6-(2-Amino-quinolin-8-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenyl}-carbamicacid tert-butyl ester. To a solution of 2-amino-quinolin-8-ol (1.2 g,8.0 mmol, Aldrich) in THF (75 mL) at 0° C. was added sodium hydride(0.21 g, 8.8 mmol, 95% dry, Aldrich) in portions. After stirring for 15min at 0° C., a solution of[2-(6-chloro-pyrimidin-4-yl)-5-trifluoromethyl-phenyl]-carbamic acidtert-butyl ester (3.0 g, 8.0 mmol) in THF (25 mL) was slowly added. Thereaction was allowed to warm to room temperature and stirred for 2 h.The reaction was cooled to 0° C., and additional NaH (0.11 g, 4.4 mmol,95% dry, Aldrich) was added in portions. The reaction was allowed towarm to room temperature and stirred for 2 h and then cooled to 0° C.and H₂O (10 mL) was added carefully. The reaction mixture wasconcentrated in vacuum and the residue was dissolved in ethyl acetate(50 mL), washed with H₂O (2×25 mL), 1 N NaOH (20 mL), H₂O (2×50 mL),dried over MgSO₄, filtered and concentrated in vacuum. Purification bysilica gel chromatography (2:1, EtOAc:hexanes) afforded the titlecompound as a white solid. Mp: 194-195° C. MS (ESI, pos. ion) m/z: 498(M+1). Anal. Calcd for C₂₅H₂₂F₃N₅O₃: C, 60.36; H14.46; F, 11.46; N,14.08. Found: C, 60.56; H, 4.50; F, 11.57; N, 14.11.

EXAMPLE 149

8-[6-(2-Amino-4-tri fluoromethyl-phenyl)-pyrimidin-4-yl oxy]-quinolin-2-ylamine. To{2-[6-(2-amino-quinolin-8-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenyl}-carbamicacid tert-butyl ester, (Example 148), (0.10 g, 0.20 mmol) was added 4 MHCl in dioxane (15 mL). The reaction mixture was stirred for 16 h andthen concentrated in vacuum. The residue was dissolved in EtOAc (20 mL)and washed with NaHCO₃ (2×50 mL), dried over Na₂SO₄, filtered andconcentrated in vacuum. Purification by silica gel chromatography (2: 1,EtOAc: hexanes) afforded the title compound as thick yellow oil. Mp:233-234° C. MS (ESI, pos. ion) m/z: 398 (M+1).

EXAMPLE 150

{2-[6-(2-Acetylamino-benzothiazol-4-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenyl}-carbamicacid tert-butyl ester. To a solution ofN-(4-hydroxybenzo-thiazol-2-yl)-acetamide, (Example 144(c)), (96 g, 27mmol) in DMF (200 mL) was added NaH (0.68 g, 28 mmol, 60% dispersion inoil, Aldrich) and the mixture was stirred at 0° C. for 15 min.[2-(6-Chloro-pyrimidin-4-yl)-5-trifluoromethyl-phenyl]-carbamic acidtert-butyl ester, (Example 148(b)), (10 g, 26 mmol) was then added andthe reaction mixture was allowed to warm to room temperature, andstirred for 4.5 h. The reaction mixture was quenched with H₂O (200 mL)and poured into a solution containing 30% ethyl acetate/hexanes (500 mL)and 1 N NaOH (800 mL). A white precipitate which formed was filtered andthe filtercake was washed with H₂O (100 mL) and 10% EtOAc/hexanes (100mL). The filtercake was dried in vacuum, redissolved in anacetone/methanol mixture and adsorbed on silica gel. Purification bysilica gel chromatography (2:1 EtOAc/hexanes) afforded the product as awhite crystalline solid. Mp: 194-195° C. MS (ESI, pos. ion) m/z: 546(M+1).

EXAMPLE 151

N-{4-[6-(2-Amino-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide.To{2-[6-(2-acetylamino-benzothiazol-4-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenyl}-carbamicacid tert-butyl ester, (Example 150) (0.35 g, 0.60 mmol) was added 4 MHCl in dioxane (25 mL). The mixture was stirred for 16 h and then wasconcentrated in vacuum. The residue was dissolved in ethyl acetate (40mL) and washed with saturated NaHCO₃ (2×70 mL), dried over Na₂SO₄ andconcentrated in vacuum. Purification by silica gel chromatography (2:1,EtOAc:hexanes) afforded the title compound as thick yellow oil. Mp:160-161° C. MS (ESI, pos. ion) m/z: 446 (M+1). Anal. Calcd forC₂₀H₁₄F₃N₅O₂S_(0.4)H₂O: C, 53.07; H, 3.30; F, 15.47; N, 12.59. Found: C,53.12; H, 3.27; F, 15.19; N, 12.70.

EXAMPLE 152

N-{2-[6-(2-Acetylamino-benzothiazol-4-yloxy)-pyrimidin-4-yl]-5-trifluoro-methyl-phenyl}-acetamide.To a suspension ofN-{4-[6-(2-amino-4-trifluoro-methyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide,(Example 151), (0.20 g, 0.50 mmol) in toluene (10 mL) was added aceticanhydride (0.090 g, 0.80 mmol, Aldrich). The reaction mixture was heatedat reflux for 3 h, allowed to cool to room temperature and concentratedin vacuum. The residue was dissolved in EtOAc (20 mL) and washed withsatd NaHCO₃ (2×20 mL), dried over Na₂SO₄, filtered and concentrated invacuum. Purification by silica gel chromatography (1:1:0.5CH₂Cl₂/hexanes/EtOAc) provided the title compound as an off-white solid.Mp: 259-261° C. MS (ESI, pos. ion) m/z: 488 (M+1).

EXAMPLE 153

N-{2-[6-(2-Acetylamino-benzothiazol-4-yloxy)-pyrimidin-4-yl]-5-trifluoro-methyl-phenyl}-2-cyclohexyl-acetamide.To a solution of cyclohexylacetic acid (0.16 g, 1.1 mmol, Aldrich) inCH₂Cl₂ (5 mL) and DMF (2 drops) was added oxalyl chloride (0.84 mL, 1.7mmol, 2 M solution in CH₂Cl₂, Aldrich) dropwise. After the addition wascomplete and gas evolution ceased, the reaction mixture was heated at40° C. for 30 min. The excess oxalyl chloride and CH₂Cl₂ was evaporatedin vacuum to provide a yellow oil. The oil was added dropwise to asolution ofN-{4-[6-(2-amino-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide,(Example 151), (0.25 g, 0.56 mmol) in acetone (15 mL) and triethylamine(0.20 mL, 1.7 mmol, Aldrich) at room temperature. The reaction mixturewas stirred for 16 h and then concentrated in vacuum. The residue wasdissolved in EtOAc (10 mL) and washed with satd NaHCO₃ (2×20 mL), driedover Na₂SO₄, filtered and concentrated in vacuum. Purification by silicagel chromatography (1:1:0.5 CH₂Cl₂/hexanes/EtOAc) provided the titlecompound as a white crystalline solid. Mp: 288-289° C. MS (ESI, pos.ion) m/z: 570 (M+1).

ADDITIONAL EXAMPLES

Following the procedure described above in Example 153, or with slightmodifications thereof, and following procedures familiar to one ofordinary skill in the art, the following examples were prepared fromcommercially available reagents:

MS (ESI, pos. ion) Melting Example Structure m/z Point ° C. 154

618 (M + 1) 276-277 155

556 (M + 1) 299-302 156

530 (M + 1) 273-275 157

551.1 (M + 1) >295 158

551.1 (M + 1) 294-295

EXAMPLE 159

N-(4-{6-[2-(Cyclohexylmethyl-amino)-4-trifluoromethyl-phenyl]-pyrimidin-4-yloxy}-benzothiazol-2-yl)-acetamide.To a solution ofN-{4-[6-(2-amino-4-tri-fluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide,(Example 151), (0.17 g, 0.3 mmol) in 1,2-dichloroethane (10 mL) wasadded cyclohexanecarboxaldehyde (0.1 g, 0.9 mmol, Aldrich) and themixture was stirred at 40° C. for 2 h. Sodium triacetoxyborohydride(0.40 g, 1.9 mmol, Aldrich) was added and the reaction mixture wasstirred for 18 h at room temperature. After the addition of water (2mL), the reaction mixture was evaporated in vacuum. The residue wasdiluted with H₂O (10 mL) and extracted with EtOAc (2×20 mL), dried overNa₂SO₄, filtered, and concentrated in vacuum. Purification of theresidue by silica gel chromatography (6:1, hexanes: EtOAc) afforded thetitle compound as an yellow solid. Mp: 232-234° C. MS(ESI, pos. ion)m/z: 542 (M+1).

EXAMPLE 160

4-({2-[6-(2-Acetylamino-benzothiazol-4-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenylamino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester. The title compound was prepared fromN-{4-[6-(2-amino-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide(Example 151) and N-Boc-4-piperidinylcarboxaldehyde according theprocedure described in Example 159. MS(ESI, pos. ion) m/z: 643 (M+1).

EXAMPLE 161

N-[4-(6-{2-[(Piperidin-4-ylmethyl)-amino]-4-trifluoromethyl-phenyl}-pyrimidin-4-yloxy)-benzothiazol-2-yl]-acetamide.To a solution of4-({2-[6-(2-acetylamino-benzothiazol-4-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenylamino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester, (Example 160), (0.20 g, 0.30 mmol) in CH₂Cl₂ (10mL) was added trifluoroacetic acid (30 mL, Aldrich). The reactionmixture was allowed to stir for 3 h at room temperature and thenconcentrated in vacuum. The residue was dissolved in EtOAc (30 mL),washed with satd NaHCO₃ (2×30 mL), dried over Na₂SO₄, filtered andconcentrated in vacuum. Purification by silica gel chromatography (2:1,EtOAc:hexanes) afforded the title compound as yellow film. MS (ESI, pos.ion) m/z: 543 (M+1).

EXAMPLE 162

{2-[6-(Quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenyl}-carbamicacid tert-butyl ester. (Analogous to the procedures of Boisnard, S.;Carbonnelle, A. C.; Zhu, J. Org Let. 2001, 3, 2061-2064 and Hewawasam,P.; Meanwell, N. A. Tetrahedron Lett. 1994, 35, 7303). To a 1-L,three-neck, round-bottom flask containing(3-trifluoromethylphenyl)carbamic acid tert-butyl ester (15 g, 57 mmol)in THF (400 mL) stirred at −40° C. was added sec-BuLi (100 mL, 1.3 M incyclohexane, Aldrich) over 20 min. The mixture was stirred for 1 h at−40° C. and then cooled to −78° C. Trimethyl borate (26 mL, 230 mmol,Aldrich) was added over 10 min. The reaction mixture was allowed to warmto room temperature and stirred for 0.5 h and then quenched with aq 1 MNaH₂PO₄ (200 mL) and H₂O (200 mL). The solution was concentrated toremove the THF and cyclohexane, and the aqueous residue was extractedwith EtOAc (2×250 mL). The combined extracts were washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuum to afford ayellow foam (16 g). To a 250-mL, round-bottom flask equipped with areflux condenser was added the yellow foam (6.2 g),7-(6-chloro-pyrimidin-4-yloxy)-quinoline, (Example 102(a)), (3.0 g, 11.6mmol), toluene (50 mL), EtOH (12 mL) and aq K₂CO₃ (35 mL, 1 M). Theflask was carefully evacuated and then backfilled twice with N₂.Tetrakis-(triphenylphosphine)palladium(0) (0.67 g, 0.58 mmol, Strem) wasthen added and the flask was again evacuated and backfilled twice withN₂. The mixture was then vigorously stirred at 80° C. for 17 h. Afterthe reaction was allowed to cool to room temperature, 1 N NaOH (100 mL)and H₂O (100 mL) were added. The mixture was extracted with EtOAc (3×100mL) and the combined extracts were washed with H₂O (2×100 mL), brine(1×100 mL), dried over Na₂SO₄, filtered and concentrated in vacuum. Theresidue was diluted with EtOAc and concentrated onto silica gel.Purification by silica gel chromatography (gradient, 35 to 70%EtOAc/hexanes) afforded the title compound as a pale-yellow solid. Mp:159-162° C. MS (ESI, pos. ion) m/z: 483.2 (M+1).

EXAMPLE 163

2-[6-(Quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenylamine.To a round-bottom flask was added{2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenyl}-carbamicacid tert-butyl ester, (Example 162), (3.2 g, 6.6 mmol) and CH₂Cl₂ (100mL). The mixture was cooled to 0° C. and trifluoroacetic acid (25 mL)was added. After stirring for 5 min at 0° C., the mixture was allowed towarm to room temperature and stirred for 1.5 h. The reaction mixture wasconcentrated in vacuum and diluted with CH₂Cl₂ (200 mL) and satd NaHCO₃(200 mL). The phases were separated and the aqueous phase was extractedwith CH₂Cl₂ (100 mL). The combined extracts were washed with aq NaHCO₃(20% satd NaHCO₃/H₂O), H₂O, brine and then dried over Na₂SO₄, filteredand concentrated onto silica gel. Purification by silica gelchromatography (gradient, 40 to 75% EtOAc/hexanes) afforded the titlecompound as a yellow solid. Mp: 193-194° C. MS (ESI, pos. ion) m/z:383.2 (M+1).

EXAMPLE 164

Cyclohexylmethyl-{2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenyl}-amine.To a solution of2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenylamine,(Example 163), (0.40 g, 1.1 mmol) in 1,2-dichloroethane (11 mL) wasadded cyclohexanecarboxaldehyde (0.32 mL, 2.6 mmol, Aldrich) and themixture was stirred at room temperature for 18 h. NaBH(OAc)₃ (0.55 g,2.6 mmol) was added and stirring was continued for 8 h at 40° C. Thereaction was diluted with satd NaHCO₃ and H₂O, and extracted with EtOAc(2×75 mL). The combined extracts were washed with H₂O (75 mL) and brine(75 mL), dried over Na₂SO₄, filtered and concentrated onto silica gel.Purification by silica gel chromatography (gradient, 10 to 40%EtOAc/hexanes) afforded the title compound as a yellow solid. Mp:137-138° C. MS (ESI, pos. ion) m/z: 479.2 (M+1).

ADDITIONAL EXAMPLES

Following the procedure described in Example 164, or with slightmodifications thereof, and following procedures familiar to one ofordinary skill in the art, the following examples were prepared fromcommercially available reagents:

MS (ESI, pos. ion) Melting Example Structure m/z Point ° C. 165

453.2 (M + 1)  98-102 166

473.5 (M + 1) 108-110 167

529.2 (M + 1) 62-65 168

474.1 (M + 1) 132-133

EXAMPLE 169

(a) 4-Fluoro-6-[4-(trifluoromethyl)phenyl]pyrimidine. To a 500-mL,round-bottomed flask was added4-chloro-6-[4-trifluoromethyl)phenyl]pyrimidine, (Example 2(a), MethodA), (3.0 g, 11 mmol), potassium fluoride (5.4 g, 93 mmol, Aldrich) andanhydrous DMSO (25 mL). The reaction mixture was stirred at 100° C. for4 h under a N₂ atmosphere. The mixture was diluted with water (200 mL)and extracted with EtOAc (3×50 mL). The combined extracts were driedover Na₂SO₄, filtered and concentrated in vacuum. Purification by silicagel chromatography with gradient from 5% to 10% ethyl acetate in hexanesafforded the title compound as a white crystalline solid. MS (ESI, pos.ion) m/z: 243 (M+1).

(b) 6-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-isoquinoline. Toa 15-mL, round-bottom flask was added4-fluoro-6-(4-trifluoromethyl-phenyl)-pyrimidine (0.18 g, 0.74 mmol),isoquinolin-6-ol (0.060 g, 0.41 mmol, MonomerChem), K₂CO₃ (0.11 g, 0.82mmol) and DMF (5 mL). The mixture was stirred at room temperature for 48h and then at 60° C. for 2 h. After the reaction mixture was allowed tocool to room temperature, it was poured into a solution of satd NaHCO₃(50 mL) and H₂O (50 mL). The mixture was extracted with EtOAc (2×75 mL)and the combined extracts were washed with H₂O (3×50 mL). The organicextracts were washed with brine (50 mL) to give an emulsion, which wasfiltered through Celite®. The phases of the filtrate were separated andthe organic phase was dried over Na₂SO₄, filtered and concentrated ontosilica gel. Purification by silica gel chromatography (gradient, 10 to50% EtOAc/hexanes) afforded the title compound as an off-white solid(0.058 g, 39%). Mp: 195-196° C. MS (ESI, pos. ion) m/z: 368.2 (M+1).

EXAMPLE 170

4-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-isoquinoline. Thetitle compound was prepared from4-fluoro-6-(4-trifluoromethyl-phenyl)-pyrimidine (Example 169(a) andisoquinolin-4-ol (MonomerChem) analogous to the conditions described inExample 169(b). Mp: 206-211° C. MS (ESI, pos. ion) m/z: 368.2 (M+1).

EXAMPLE 171

N-{2-[6-(Quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenyl}-acetamide.To a solution of2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenylamine,(Example 163), (0.25 g, 0.65 mmol) in 1,2-dichloroethane (6.5 mL) wasadded acetic anhydride (0.15 mL, 1.6 mmol). The mixture was stirred atroom temperature for 18 h and then treated with satd NaHCO₃ and H₂O. Themixture was extracted with EtOAc (2×75 mL) and the combined extractswere washed with H₂O (75 mL) and brine (75 mL), dried over Na₂SO₄,filtered, and concentrated onto silica gel. Purification by silica gelchromatography (gradient, 10 to 40% EtOAc/hexanes) afforded the titlecompound as a yellow solid. Mp: 137-138° C. MS (ESI, pos. ion) m/z:479.2 (M+1).

EXAMPLE 172

N-{2-[6-(Quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenyl}-methanesulfonamide.To a solution of2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenylamine,(Example 163), (0.25 g, 0.65 mmol), N,N-diisopropylethylamine (0.57 mL,3.3 mmol) in 1,2-dichloroethane (6.5 mL) was added methanesulfonylchloride (0.12 mL, 1.6 mmol, Aldrich). The mixture was stirred at 40° C.for 72 h. After cooling to room temperature, the reaction mixture wastreated with satd NaHCO₃ and H₂O and extracted with EtOAc (2 ×75 mL).The combined extracts were washed with H₂O (75 mL) and brine (75 mL),dried over Na₂SO₄, filtered, and concentrated onto silica gel.Purification by silica gel chromatography (gradient, 30 to 60%EtOAc/hexanes) afforded a pale yellow solid. To the solid was added MeOH(5 mL), CH₂Cl₂ (5 mL) and K₂CO₃ (0.050 g). The reaction mixture wasstirred at room temperature for 24 h and then diluted with H₂O andextracted with EtOAc (2×75 mL). The combined extracts were washed withH₂O (75 mL), brine (75 mL), dried over Na₂SO₄, filtered, andconcentrated onto silica gel. Purification by silica gel chromatography(gradient, 30 to 60% EtOAc/hexanes) afforded the title compound as awhite solid. Mp: 203-204° C. MS (ESI, pos. ion) m/z: 461.0 (M+1).

EXAMPLE 173

N-{2-[6-(Quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenyl}-benzenesulfonamide.The title compound was prepared from2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenylamine,(Example 163) and phenylsulfonyl chloride (Aldrich) analogous to theconditions described in Example 172. Mp: 168-170° C. MS (ESI, pos. ion)m/z: 523.1 (M+1).

EXAMPLE 174

7-[6-(2-Bromo-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinoline. Toa 15-mL, round-bottomed flask was added CuBr₂ (0.14 g, 0.63 mmol,Aldrich) and CH₃CN (5 mL). Isoamyl nitrite (0.11 mL, 0.78 mmol, Aldrich)was added and the mixture was stirred for 10 min at room temperature bycooling with a water bath.2-[6-(Quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenylamine,(Example 163), (0.20 g, 0.52 mmol) was added in portions over 1 h. Thereaction was stirred at room temperature for 1.5 h, at 65° C. for 2 hand then at room temperature for 72 h. The reaction mixture was dilutedwith CH₂Cl₂, filtered through Celite® and the filtercake was washed withCH₂Cl₂. The filtrate was concentrated onto silica gel. Purification bysilica gel chromatography (gradient, 0.5 to 2.5% MeOH (2 M inNH₃)/CH₂Cl₂) afforded the title compound as a white solid. Mp: 185-187°C. MS (ESI, pos. ion) m/z: 447.9 (M+1).

EXAMPLE 175

N-{4-[6-(2-Bromo-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide.To a solution of CuBr₂ (0.15 g, 0.67 mmol) in CH₃CN (8 ML) was addedisoamyl nitrite (0.11 mL, 0.84 mmol). The mixture was stirred for 10 minat room temperature and thenN-{4-[6-(2-amino-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide(Example 151) was added in portions over 40 min. The reaction mixturewas stirred for 1 h at room temperature, 3 h at 65° C. and 16 h at roomtemperature. The mixture was diluted with MeOH and concentrated. It wasthen diluted with MeOH (2 M in NH3) and concentrated onto silica gel.Purification by silica gel chromatography (gradient, 0.5 to 1.7% MeOH (2M in NH₃)/CH₂Cl₂) afforded the title compound as a white solid. Mp:259.6-259.8° C. MS (ESI, pos. ion) m/z: 510.8 (M+1).

EXAMPLE 176

N-{4-[6-(2-Chloro-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide.To a solution of CuCl₂ (0.090 g, 0.67 mmol, Aldrich) in CH₃CN (8 mL) wasadded isoamyl nitrite (0.11 mL, 0.84 mmol, Aldrich) and the mixture wasstirred for 10 min by cooling with a 24° C. water bath.N-{4-[6-(2-Amino-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide,(Example 151), (0.25 g, 0.56 mmol) was added in portions over 40 min.The reaction mixture was stirred at room temperature for 1 h, at 65° C.for 3 h and then at room temperature for 16 h. The mixture wasconcentrated and then diluted with MeOH (2 M in NH₃) and concentratedonto silica gel. Purification by silica gel chromatography (gradient,0.5 to 1.7% MeOH (2 M in NH₃)/CH₂Cl₂) afforded the title compound as awhite solid. Mp: 263-264° C. MS (ESI, pos. ion) m/z: 465.1 (M+1).

EXAMPLE 177

N-{4-[6-(2-Iodo-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide.ToN-{4-[6-(2-amino-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide,(Example 151), (0.25 g, 0.56 mmol) was added CsI (0.15 g, 0.56 mmol,Aldrich), 12 (0.071 g, 0.28 mmol, Aldrich), CuI (0.032 g, 0.17 mmol,Aldrich) and ethylene glycol dimethyl ether (6 mL). To the mixture wasadded isoamyl nitrite (0.45 mL, 3.4 mmol, Aldrich) and the reaction wasstirred for 1 h at room temperature, at 65° C. for 3 h, and then at roomtemperature for 18 h. The reaction mixture was diluted with MeOH (2 M inNH₃) and concentrated. The residue was taken up in MeOH and concentratedonto silica gel. Purification by silica gel chromatography (gradient,0.4 to 1.3% MeOH (2 M in NH₃)/CH₂Cl₂) afforded the title compound as awhite solid. Mp: 242-243° C. MS (ESI, pos. ion) m/z: 557.0 (M+1).

EXAMPLE 178

(a) 4-(3-Bromo-phenoxy)-6-(4-trifluoromethyl-phenyl)-pyrimidine. Sodiumhydride (0.680 g, 17 mmol, 60% suspension in mineral oil, Aldrich) wasadded in small portions to a solution of 3-bromophenol (2.595 g, 15mmol, Aldrich) in DMF (20 mL) and the mixture was stirred at roomtemperature for 0.5 h.(4-Chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), MethodA), (2.586 g, 10 mmol) was then added and the mixture was stirred atroom temperature for 18 h. The solvent was evaporated under vacuum, theresidue was dissolved in EtOAc, washed with 1 N NaOH and water, driedover MgSO₄, and filtered. The filtrate vas evaporated under vacuum andthe residue recrystallized from EtOAc/hexanes to give the title compoundas white needles. MS (ESI, pos. ion) m/z: 397.0 (M+1).

(b) 4-(3-Pyridin-3-yl-phenoxy)-6-(4-trifluoromethyl-phenyl)-pyrimidine.To a slurry of4-(3-bromo-phenoxy)-6-(4-trifluoromethyl-phenyl)-pyrimidine (0.395 g, 1mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (0.488 g,1.5 mmol, Lancaster), potassium carbonate (0.106 g, 1 mmol), water (1.2mL), EtOH (0.8 mL) and dimethoxyethane (2.8 mL) was added (Ph₃P)₂PdCl₂(0.032 g, 0.075 mmol, Strem) and the mixture was heated in a microwavesynthesizer at 120° C. for 15 min with stirring under nitrogenatmosphere. The reaction mixture was allowed to cool to roomtemperature, diluted with EtOAc (100 mL), washes with 1 N NaOH andwater, dried over MgSO₄, and filtered. The filtrate was evaporated undervacuum and the residue purified by silica gel chromatography (CHCl₃) togive the title compound as an oil. The oil was crystallized fromEtOAc/hexanes to give pale yellow needles. Mp: 66° C. MS (ESI, pos. ion)m/z: 394 (M+1).

EXAMPLE 179

4-(Benzo[b]thiophen-4-yloxy)-6-(4-trifluoromethyl-phenyl)-pyrimidine.Sodium hydride (0.104 g, 2.6 mmol, 60% suspension in mineral oil,Aldrich) was added in small portions to a solution ofbenzo[b]thiophen-4-ol (0.3 g, 2 mmol, prepared according WO 01/68653) inDMF (4 mL) and the mixture was stirred at room temperature for 0.5 h.(4-Chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), MethodA), (0.776 g, 3 mmol) was then added and the mixture was stirred at roomtemperature for 18 h. The solvent was evaporated under vacuum, theresidue was dissolved in EtOAc (50 mL), washed with 1 N NaOH and water,dried over MgSO₄, and filtered. The filtrate was evaporated under vacuumand the residue purified by silica gel chromatography (10% EtOAc inhexanes) to give the title compound. Mp: 122.3-122.4° C. MS (ESI, pos.ion) m/z: 373.1 (M+1).

EXAMPLE 180

(a) Hydroxy-benzothiazole-2-carboxylic acid amide. To a suspension of4-methoxy-benzothiazole-2-carboxylic acid amide (0.244 g, 1.175 mmol,prepared according to White, E. H. and Worter, H.; J. Org Chem. 1966,31, 1484-1488) in anhydrous benzene (25 mL) was added AlCl₃ (0.939 g, 7mmol, Aldrich) in small portions with stirring at room temperature. Thereaction mixture was heated at reflux for 2 h with stirring undernitrogen atmosphere, quenched with water (2.5 mL) by cooling with an icebath and neutralized with excess of solid K₂CO₃. The mixture wasfiltered and the filter cake was washed with CHCl₃ (4×). The combinedorganic extracts were washed with water, dried over MgSO₄, and filtered.The filtrate was evaporated under vacuum to give the title compound as abrown solid. MS (ESI, pos. ion) m/z: 195.2 (M+1).

(b)4-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazole-2-carboxylicacid amide. The title compound was prepared fromhydroxy-benzothiazole-2-carboxylic acid amide and4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), MethodA) analogous to the conditions described in Example 179, and isolated asa white amorphous solid. MS (ESI, pos. ion) m/z: 417.3 (M+1).

EXAMPLE 181

(a) 4-Methoxy-benzothiazole-2-carboxylic acid methyl ester. To asuspension of 4-methoxy-benzothiazole-2-carboxylic acid (16.74 g, 80mmol, prepared according to White, E. H. and Worter, H.; J. Org. Chem.1966, 31, 1484-1488) in MeOH (160 mL) was added dropwise SOCl₂ (9.6 mL)and the mixture was stirred at room temperature for 18 h. The reactionmixture containing a white precipitate was cooled at −10° C. for 4 h andfiltered. The precipitate was washed with cold MeOH (10 mL) and driedunder vacuum to give the title compound as a white solid. MS (ESI, pos.ion) m/z: 224 (M+1).

(b) 4-Methoxy-benzothiazole-2-carboxylic acid dimethylamide. To asolution of 4-methoxy-benzothiazole-2-carboxylic acid methyl ester(0.446 g, 2 mmol) in MeOH (10 mL) was added 2M solution of dimethylaminein THF (3 mL, 6 mmol, Aldrich) and the mixture was stirred at roomtemperature for 3 h. Evaporation of the solvent under vacuum gave thepure title compound as a white solid. MS (ESI, pos. ion) m/z: 237 (M+1).

(c) 4-Hydroxy-benzothiazole-2-carboxylic acid dimethylamide. The titlecompound was prepared by treatment of4-methoxy-benzothiazole-2-carboxylic acid dimethylamide with AlCl₃ underthe conditions of Example 180(a) and isolated as brown crystals afterrecrystallization from EtOAc. MS (ESI, pos. ion) m/z: 223.3 (M+1).

(d)4-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazole-2-carboxylicacid dimethylamide. The title compound was prepared from4-hydroxy-benzothiazole-2-carboxylic acid dimethylamide and(4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), MethodA) analogous to the conditions described in Example 179 and isolated aswhite crystals after recrystallization from EtOAc. Mp: 152.5-152.6° C.MS (ESI, pos. ion) m/z: 445.4 (M+1).

EXAMPLE 182

(a) Imidazo[1,2-a]pyridin-8-ol. To a solution of2-amino-3-hydroxypyridine (1.65 g, 15 mmol, Aldrich) in 30 mL EtOH wasadded chloroacetaldehyde (2.0 mL, 15.7 mmol, 50 wt. % solution in water,Aldrich) and the mixture was heated at reflux for 18 h. The reactionmixture was cooled with an ice bath and the precipitated white solid wasfiltered, rinsed with cold EtOH and dried under vacuum to give the titlecompound. MS (ESI, pos. ion.) m/z: 135 (M+1)

(b)8-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-imidazo[1,2-a]pyridinetrifluoroacetate. A solution of4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), MethodA), (46.2 m g, 0.18 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (40 μl,0.26 mmol, Aldrich) and imidazo[1,2-a]pyridin-8-ol (24 mg, 0.18 mmol) inCH₃CN (0.5 mL) was heated in a microwave synthesizer at 180° C. for 15min. The reaction mixture was allowed to cool to room temperature,evaporated under vacuum and the residue purified by prep. LC (10-90%CH₃CN/H₂O modified with 0.1% TFA) to give the title compound as a whitesolid. MS (ESI, pos. ion.) m/z: 357 (M+1).

EXAMPLE 183

(a) 2,6-Diamino-benzothiazol-4-ol hydrochloride. A solution ofN-(6-amino-4-methoxy-benzothiazol-2-yl)-acetamide (350 mg, 1.8 mmol,Asinex) in hydrobromic acid (2 mL, 48 wt. % in water, Aldrich) washeated in a microwave synthesizer at 170° C. for 10 min. The reactionmixture was allowed to cool to room temperature and the volatiles wereremoved under reduced pressure. The residue was treated with EtOAc (10mL) and 1 N NaOH (5 mL). The aqueous layer was separated and treatedwith 2 N HCl (5 mL), and extracted with EtOAc (2×20 mL). The combinedorganic extracts were dried over Na₂SO₄, filtered and evaporated invacuum to afford the title compound as a brown solid. MS (ESI, pos.ion.) m/z: 182 (M+1).

(b)4-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazole-2,6-diaminetrifluoroacetate. To a solution of 2,6-diamino-benzothiazol-4-olhydrochloride (144 mg, 0.55 mmol) in MeOH (1 mL) and THF (1 mL) wasadded N,N-diisopropylethylamine (0.29 mL, 1.65 mmol, Aldrich) anddi-tert-butyl dicarbonate (130 mg, 0.61 mmol, Aldrich) with stirring at0° C. The reaction mixture was stirred at room temperature for 18 h,diluted with EtOAc and washed with satd NaHCO₃. The organic layer wasseparated, dried over Na₂SO₄, filtered and evaporated in vacuum. Thesolid residue was dissolved in DMF (2 mL) and treated with K₂CO₃ (138mg, 1 mmol) and 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine,(Example 2(a), Method A), (142 m g, 0.55 mmol). The resulting mixturewas heated at 80° C. with stirring for 1 h, allowed to cool to roomtemperature, filtered and rinsed with MeOH. The filtrate was evaporatedunder vacuum and the resulting brown solid was dissolved indichloromethane (5 mL) and trifluoroacetic acid (2.5 mL). The mixturewas stirred at room temperature for min, the solvents were evaporatedunder vacuum, and the residue was purified by prep. LC (10-90% CH₃CN/H₂Omodified with 0.1% TFA) to give the title compound as a white solid. Mp:220-221° C. MS (ESI, pos. ion.) m/z: 404 (M+1).

EXAMPLE 184

(a) N-(6-Dimethylamino-4-methoxy-benzothiazol-2-yl)-acetamide. To asolution of N-(6-amino-4-methoxy-benzothiazol-2-yl)-acetamide (156 mg,0.66 mmol, Asinex) and formaldehyde (0.5 mL, 37 wt. % solution in water,Aldrich) in MeOH (2 mL) was added glacial acetic acid (2 drops), andsodium triacetoxyborohydride (557 mg, 2.64 mmol, Aldrich), and theresulting mixture was stirred at room temperature for 5 h. The reactionmixture was diluted with EtOAc and washed with 1 N NaOH and water. TheEtOAc layer was separated, dried over Na₂SO₄, filtered and evaporated invacuum to give the crude title compound, which was used in the next stepwithout additional purification. MS (ESI, pos. ion.) m/z: 266 (M+1).

(b)N-{6-Dimethylamino-4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamidetrifluoroacetate. To a solution of ethanethiol (0.2 mL, 2.70 mmol,Aldrich) in DMF (3 mL) was added NaH (87 mg, 3.45 mmol, Aldrich) and themixture was stirred at 0° C. for 10 min. A solution of the crudeN-(6-dimethylamino-4-methoxy-benzothiazol-2-yl)-acetamide from step (a)above in DMF (3 mL) was then added and the mixture was heated at 130° C.for 3 h. The reaction mixture was allowed to cool to room temperature,concentrated to dryness under reduced pressure, and the residue wastreated with EtOAc and satd NH₄Cl. The EtOAc layer was separated, driedover Na₂SO₄, filtered, and evaporated in vacuum. The residue wasdissolved in DMF (3 mL) and mixed with potassium carbonate (284 mg, 2.07mmol) and 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example2(a), Method A), (266 mg, 1.03 mmol). The mixture was heated at 80° C.for 3 h, allowed to cool to room temperature and filtered. The filtratewas evaporated under vacuum and the residue purified by prep. LC (10-90%CH₃CN/H₂O modified with 0.1% TFA) to give the title compound as a yellowsolid. Mp: 243-245° C. MS (ESI, pos. ion.) m/z: 474 (M+1).

EXAMPLE 185

{4-[6-(4-Trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-carbamicacid methyl ester. To a solution of4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine,(Example 65) (100 mg, 0.26 mmol) in pyridine (2 mL) was added methylchloroformate (28 mg, 0.29 mmol, Aldrich) at 0° C. The reaction mixturewas stirred at room temperature for 2 h, diluted with EtOAc and washedwith 1 N NaOH and water. The EtOAc layer was separated, dried overNa₂SO₄, filtered and evaporated in vacuum. Purification of the residueby silica gel chromatography with gradient: 40 to 80% EtOAc in hexanesgave the title compound as an off white solid. MS (ESI, pos. ion.) m/z:447 (M+1).

EXAMPLE 186

(a) (4-Methoxy-benzothiazol-2-yl)-carbamic acid benzyl ester. To astirred solution of 4-methoxy-benzothiazol-2-ylamine (4.2 g, 23.4 mmol,Aldrich) in pyridine (20 mL) at 90° C. was added benzyl chloroformate(10 mL, 71.2 mmol, Aldrich) in three portions over 6 h. The reactionmixture was then evaporated to dryness, the residue was treated withbrine (100 mL) and extracted with dichloromethane (3×100 mL). Thecombined organic extracts were dried over Na₂SO₄, filtered andevaporated in vacuum. Purification of the residue by silica gelchromatography (3:1 dichloromethane/EtOAc) gave the title compound as anoff-white solid. MS (ESI, pos. ion.) m/z: 315 (M+1).

(b) (7-Iodo-4-methoxy-benzothiazol-2-yl)-carbamic acid benzyl ester. Toa mixture of (4-methoxy-benzothiazol-2-yl)-carbamic acid benzyl ester(628 mg, 2 mmol) and sodium acetate (498 mg, 6 mmol) in glacial aceticacid (10 mL) was added iodine monochloride (648 mg, 4 mmol, Aldrich)with stirring at 0° C. The reaction mixture was stirred at roomtemperature for 15 h and diluted with water (200 mL). The precipitatewas filtered, washed with water, dissolved in EtOAc, and washed withsatd aq. Na₂S₂O₃. The organic layer was separated, dried over Na₂SO₄,filtered and evaporated in vacuum to give the title compound as a darkbrown solid, which was used in the next step without additionalpurification. MS (ESI, pos. ion.) m/z: 441 (M+1).

(c) 4-Methoxy-7-pyridin-4-yl-benzothiazol-2-ylamine. A mixture of(7-iodo-4-methoxy-benzothiazol-2-yl)-carbamic acid benzyl ester (197 mg,0.45 mmol), pyridine-4-boronic acid (61 mg, 0.49 mmol, Aldrich), and Pd(PPh₃)₄ (51 mg, 0.04 mmol, Aldrich) in 1,4-dioxane (3 mL) and 2 M Na₂CO₃(1 mL) was heated in a microwave synthesizer at 170° C. for 15 min. Themixture was allowed to cool to room temperature, diluted with EtOAc, andwashed with satd aq. NaHCO₃. The EtOAc layer was separated, dried overNa₂SO₄, filtered, and evaporated in vacuum to give the title compound asa brown solid (100 mg), which was used in next step without additionalpurification. MS (ESI, pos. ion.) m/z: 258 (M+1).

(d)7-Pyridin-4-yl-4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine.A mixture of 4-methoxy-7-pyridin-4-yl-benzothiazol-2-ylamine (100 mg,0.38 mmol) in cond HBr (0.5 mL) was heated in a microwave synthesizer at165° C. for 12 min. The reaction mixture was allowed to cool to roomtemperature and the solvents were evaporated under vacuum. To theresidue was added toluene (5 mL) and the mixture was evaporated again toafford a brown solid. The solid was dissolved in DMF (2 mL) and to thesolution were added 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine,(Example 2(a), Method A), (98 mg, 0.38 mmol) and K₂CO₃ (267 mg, 1.93mmol). The resulting mixture was heated at 80° C. for 2 h, the solventswere removed under reduced pressure and to the residue was added EtOAc(50 mL) and 1 N NaOH (10 mL). The organic phase was separated, driedover Na₂SO₄, filtered and concentrated. Purification of the residue bysilica gel chromatography with gradient: 40 to 90% EtOAc in hexanes gavethe title compound as an off white solid. MS (ESI, pos. ion.) m/z: 466(M+1).

EXAMPLE 187

(a) 2-Chloro-6-trifluoromethylpyrid-3-ylboronic acid. A solution ofN,N′-diisopropylamine (990 μL, 7.0 mmol, Aldrich) in dry THF (7.0 mL)was stirred at −78° C. and treated with n-butyllithium (1.6 M inhexanes, 3.8 mL, 6.0 mmol, Aldrich). After stirring at −78° C. for 15min, a solution of 2-chloro-6-(trifluoromethyl)pyridine (910 mg, 5.0mmol, Matrix Scientific) in dry THF (2.0 mL) was introduced and thereaction mixture was stirred for 1.5 h at −78° C. The resulting mixturewas then treated with trimethyl boratel (1.7 mL, 15 mmol, Aldrich) at−78° C. and then stirred at room temperature for 20 h. The reactionmixture was cooled to 0° C. and treated with 2 N aq HCl to reach pH 6.The organic phase was separated, and the aqueous phase was extractedwith EtOAc. The combined extracts were washed with water and brine,dried over Na₂SO₄, filtered and concentrated in vacuum to provide thetitle compound as a light-brown foam. MS (ESI, pos. ion) m/z: 224 (M−1).

(b)7-[6-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-pyrimidin-4-yloxy]-quinoline.To a suspension of 2-chloro-6-trifluoromethylpyrid-3-ylboronic acid (340mg, 1.5 mmol) and 7-(6-chloro-pyrimidin-4-yloxy)-quinoline, (Example102), (260 mg, 1.0 mmol) in toluene/EtOH (1:1, 3.0 mL) was added 2 MK₂CO₃ (2.0 mL, 4.0 mmol) and Pd(PPh₃)₄ (58 mg, 0.050 mmol, Strem). Thereaction mixture was stirred and heated in a microwave synthesizer at140° C. for 10 min. The mixture was partitioned between CH₂Cl₂ and 1 NNaOH. The organic phase was separated, and the aqueous phase wasextracted with CH₂Cl₂. The combined extracts were dried over Na₂SO₄,filtered and concentrated in vacuum. Purification by silica gelchromatography (MeOH/CH₂Cl₂ 1:120) afforded a yellow-orange solid. Thetitle compound was obtained as a white solid after recrystallizationfrom MeOH. MP: 209° C. MS (ESI, pos. ion) m/z: 403 (M+1). Anal. Calcdfor C₁₉H₁₀ClF₃N₄O: C, 56.66; H, 2.50; N, 13.91. Found: C, 56.47; H,2.53; N, 13.83.

EXAMPLE 188

3′-[6-(Quinolin-7-yloxy)-pyrimidin-4-yl]-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyltrifluoroacetate. To a solution of7-[6-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-pyrimidin-4-yloxy]-quinoline,(Example 187), (190 mg, 0.47 mmol) in DMF (4.6 mL) stirred at 60° C. wasadded piperidine (140 μL, 1.43 mmol, Aldrich). After the startingmaterial was completely consumed, the reaction mixture was concentratedin vacuum to remove the DMF. The crude product was purified by silicagel chromatography (gradient, 0 to 4% MeOH/ CH₂Cl₂) and then by HPLC toafford the title compound as a yellow foam. MS (ESI, pos. ion) m/z: 452(M+1). C₂₄H₂₀F₃N₅O: C, 63.85; H, 4.47; N, 15.51. Found: C, 63.84; H,4.49; N, 15.39.

EXAMPLE 189

Cyclohexylmethyl-{3-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-6-trifluoromethyl-pyridin-2-yl}-amine.According to the procedure described in Example 188,7-[6-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-pyrimidin-4-yloxy]-quinoline(Example 187) (110 mg, 0.27 mmol) and cyclohexanemethylamine (43 pL,0.33 mmol, Aldrich), after purification by silica gel chromatography(gradient, 0 to 3% MeOH/CH₂Cl₂) and then preparative TLC (4%MeOH/CH₂Cl₂), provided the title compound as a yellow solid. MP:151-152° C. MS (ESI, pos. ion) m/z: 480 (M+1).

EXAMPLE 190

7-[6-(2-Methoxymethoxy-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinoline.To a suspension of 2-methoxymethoxy-4-trifluoromethylphenyl-boronicacid, (Example 135(b)), (220 mg, 0.87 mmol) and7-(6-chloro-pyrimidin-4-yloxy)-quinoline, (Example 102(a)), (150 mg,0.58 mmol) in toluene/EtOH (1:4, 3.8 mL) was added 2 M K₂CO₃ (1.2 mL,2.3 mmol) and Pd(PPh₃)₄ (34 mg, 0.030 mmol, Strem). The reaction mixturewas stirred and heated by microwave synthesizer at 140° C. for 10 min.The mixture was partitioned between CH₂Cl₂ and 1 N NaOH. The organicphase was separated, and the aqueous phase was extracted with CH₂Cl₂.The combined extracts were dried over Na₂SO₄, filtered and concentratedin vacuum. Purification by silica gel chromatography (MeOH/CH₂Cl₂ 1:125and then 1:100) afforded a light-yellow gum. The title compound wasobtained as a white solid after recrystallization from MeOH. MP:98.8-99.4° C. MS (ESI, pos. ion) m/z: 428 (M+1). Anal. Calcd forC₂₂H₁₆F₃N₃O₃: C, 61.83; H, 3.77; N, 9.83. Found: C, 62.13; H, 3.87; N,9.52.

EXAMPLE 191

2-[6-(Quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenol. To astirred solution of7-[6-(2-methoxymethoxy-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinoline,(Example 190), (1.1 g, 2.5 mmol) in CH₂Cl₂ (25 mL) at −78° C. was addedborontrifluoride diethyl etherate (0.95 mL, 7.6 mmol, Aldrich). Thereaction mixture was allowed to warm to 0° C. over 1 h and then left tostir at room temperature for 16 h. The reaction mixture was quenchedwith satd NaHCO₃ at 0° C. The organic phase was separated, and theaqueous phase was extracted with CH₂Cl₂. The combined extracts werewashed with brine, dried over Na₂SO₄, filtered, and concentrated invacuum. The crude yellow solid was suspended in MeOH, collected byfiltration, washed with MeOH, and dried under high vacuum to give thetitle compound as a light-yellow solid. MP: 210.5-212.3° C. MS (ESI,pos. ion) m/z: 384 (M+1), 382 (M−1). Anal. Calcd for C₂₀H₁₂F₃N₃O₂: C,62.67; H, 3.16; N, 10.96; F, 14.87. Found: C, 62.85; H, 3.18; N, 11.02;F, 14.57.

EXAMPLE 192

(a) Trifluoro-methanesulfonic acid2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenyl ester.To a mixture of2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenol,(Example 191), (1.6 g, 4.3 mmol) and N-phenyltrifluoromethanesulfonimide(1.8 g, 5.1 mmol, Aldrich) in CH₂Cl₂/DMF (1:1, 20 mL) was addedN,N′-diisopropylethylamine (3.0 mL, 17 mmol, Aldrich) at roomtemperature with stirring. The reaction mixture was stirred at roomtemperature for 20 h, then diluted with water (20 mL). The organic phasewas separated, and the aqueous phase was extracted with CH₂Cl₂. Thecombined extracts were washed with water, dried over Na₂SO₄, filteredand concentrated in vacuum. The crude yellow solid was purified bysilica gel chromatography (MeOH/CH₂Cl₂ 1: 110) to give the titlecompound as a light-yellow solid. MS (ESI, pos. ion) m/z: 516 (M+1).

(b) 7-[6-(5-Trifluoromethyl-biphenyl-2-yl)-pyrimidin-4-yloxy]-quinoline.A mixture of trifluoromethanesulfonic acid2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethylphenyl ester(100 mg, 0.19 mmol), phenylboronic acid (36 mg, 0.29 mmol, Aldrich),K₃PO₄ (82 mg, 0.39 mmol), KBr (35 mg, 0.29 mmol) and Pd(PPh₃)₄ (11 mg,0.010 mmol, Strem) in dioxane (2.0 mL) was stirred and heated at 85° C.for 20 h. The mixture was partitioned between CH₂Cl₂ and 1 N NaOH. Theorganic phase was separated, and the aqueous phase was extracted withCH₂Cl₂. The combined extracts were dried over Na₂SO₄, filtered andconcentrated in vacuum. Purification by silica gel chromatography(gradient 0.5 to 3.0% MeOH/CH₂Cl₂) afforded the title compound as awhite amorphous solid. MS (ESI, pos. ion) m/z: 444 (M+1).

EXAMPLE 193

7-[6-(4′-Fluoro-5-trifluoromethyl-biphenyl-2-yl)-pyrimidin-4-yloxy]-quinoline.A mixture of trifluoromethanesulfonic acid2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethylphenyl ester,(Example 192(a)), (100 mg, 0.19 mmol), 4-fluorophenyl boronic acid (41mg, 0.29 mmol, Aldrich), K₃PO₄ (82 mg, 0.39 mmol), KBr (35 mg, 0.29mmol) and Pd(PPh₃)₄ (11 mg, 0.010 mmol, Strem) in dioxane (2.0 mL) wasstirred and heated by microwave synthesizer at 140° C. for 10 min. Themixture was partitioned between CH₂Cl₂ and 1 N NaOH. The organic phasewas separated, and the aqueous phase was extracted with CH₂Cl₂. Thecombined extracts were dried over Na₂SO₄, filtered and concentrated invacuum. Purification by silica gel chromatography (gradient 0.5 to 3.0%MeOH/CH₂Cl₂) afforded the title compound as a white amorphous solid. MS(ESI, pos. ion) m/z: 462 (M+1).

EXAMPLE 194

7-[6-(2-Pyridin-3-yl-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinoline.A mixture of trifluoromethanesulfonic acid2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethylphenyl ester,(Example 192(a)), (200 mg, 0.39 mmol), diethyl (3-pyridyl)borane (230mg, 1.6 mmol, Aldrich), K₃PO₄ (170 mg, 0.78 mmol), KBr (69 mg, 0.58mmol) and Pd(PPh₃)₄ (23 mg, 0.020 mmol, Strem) in dioxane (2.0 mL) wasstirred and heated by microwave synthesizer at 150° C. for 20 min. Themixture was filtered and washed with CH₂Cl₂. The filtrate wasconcentrated in vacuum to dryness. Purification by silica gelchromatography (gradient 0.5 to 4.0% MeOHI CH₂Cl₂) afforded the titlecompound as a white amorphous solid. MS (ESI, pos. ion) m/z: 445 (M+1).

EXAMPLE 195

7-{6-[2-(2-Morpholin-4-yl-ethoxy)-4-trifluoromethyl-phenyl]-pyrimidin-4-yloxy}-quinoline.A solution of 4-(2-chloroethyl)morpholine hydrochloride (58 mg, 0.31mmol, Aldrich) in DMF (1.0 mL) was stirred at room temperature andtreated with K₂CO₃ (86 mg, 0.62 mmol). After stirring for 5 min, theresulting solution was added to a mixture of2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethylphenol,(Example 191), (100 mg, 0.26 mmol) and NaH (13 mg, 0.52 mmol, 95%,Aldrich) in DMF (2.0 mL) at room temperature. The reaction mixture wasstirred at room temperature for 1 h and then heated at 70° C. for 20 h.The resulting mixture was allowed to cool to room temperature anddiluted with water. The organic phase was separated, and the aqueousphase was extracted with CH₂Cl₂. The combined extracts were washed withwater and brine, dried over Na₂SO₄, filtered and concentrated in vacuum.Purification by silica gel chromatography (gradient 0% to 4.0% MeOHWCH₂Cl₂) afforded the title compound as a white solid. MP: 132-133° C. MS(ESI, pos. ion) m/z: 497 (M+1).

EXAMPLE 196

(a)7-{6-[2-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-4-trifluoromethyl-phenyl]-pyrimidin-4-yloxy}-quinoline.A mixture of2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenol,(Example 191), (100 mg, 0.26 mmol),D-α,β-isopropylidene-glycerol-γ-tosylate (150 mg, 0.52 mmol, Fluka) andK₂CO₃ (110 mg, 0.73 mmol) was stirred and heated at 80° C. for 20 h. Theresulting mixture was allowed to cool to room temperature and dilutedwith water. The organic phase was separated, and the aqueous phase wasextracted with CH₂Cl₂. The combined extracts were washed with water andbrine, dried over Na₂SO₄, filtered and concentrated in vacuum.Purification by silica gel chromatography (gradient 0% to 4.0%MeOH/CH₂Cl₂) provided the title compound as a colorless oil. MS (ESI,pos. ion) m/z: 498 (M+1).

(b)3-{2-[6-(Quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenoxy}-propane-1,2-diol.To a solution of7-{6-[2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-4-trifluoromethyl-phenyl]-pyrimidin-4-yloxy}-quinoline(130 mg, 0.26 mmol) in MeOH (1.3 mL) stirred at room temperature wasadded water (0.4 mL) and p-toluenesulfonic acid monohydrate (25 mg, 0.35mmol, Aldrich). The reaction mixture was stirred at 60° C. for 3 h, thenat 80° C. for 1 h. The resulting mixture was allowed to cool to roomtemperature and treated with satd NaHCO₃. The reaction mixture wasextracted with CH₂Cl₂. The combined extracts were washed with water andbrine, dried over Na₂SO₄, filtered, and concentrated in vacuum.Purification by preparative TLC (MeOH/CH₂Cl₂ 40:1) provided the titlecompound as a light-yellow amorphous solid. MS (ESI, pos. ion) m/z: 458(M+1).

EXAMPLE 197

7-[6-(2-Cyclohexylmethoxy-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinoline.To a mixture of2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenol,(Example 191), (50 mg, 0.13 mmol) and K₂CO₃ (54 mg, 0.39 mmol) in DMF(2.0 mL) was added (bromomethyl)cyclohexane (20 μL, 0.14 mmol, Aldrich).The reaction mixture was stirred at 60° C. for 23 h. The resultingmixture was allowed to cool to room temperature and filtered. Thefiltrate was concentrated in vacuum and purified by silica gelchromatography (gradient: 0% to 3.0% MeOH/CH₂Cl₂) to provide the titlecompound as a white amorphous solid. MS (ESI, pos. ion) nt/z: 480 (M+1).

EXAMPLE 198

7-[6-(2-Benzyloxy-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinoline.To a mixture of2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenol,(Example 191), (50 mg, 0.13 mmol) and K₂CO₃ (54 mg, 0.39 mmol) in DMF(2.0 mL) was added benzyl bromide (17 μL, 0.14 mmol, Aldrich) and thereaction mixture was stirred at room temperature for 4 h. The resultingmixture was diluted with water and extracted with CH₂Cl₂. The combinedextracts were washed with water and brine, dried over Na₂SO₄, filteredand concentrated in vacuum. Purification by silica gel chromatography(gradient: 0% to 3.0% MeOH/CH₂Cl₂) provided the title compound as alight-yellow amorphous solid. MS (ESI, pos. ion) m/z: 474 (M+1).

EXAMPLE 199

7-[6-(4-Trifluoromethyl-2-vinyl-phenyl)-pyrimidin-4-yloxy]-quinoline. Toa solution of trifluoromethanesulfonic acid2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenyl ester,(Example 192(a)), (600 mg, 1.2 mmol) in dioxane (6.0 mL) was addedvinyltributylstannate (370 μL, 1.6 mmol, Fluka), LiCl (150 mg, 3.5 mmol,Aldrich), Pd(PPh₃)₄ (27 mg, 0.02 mmol, Strem) and a few crystals of2,6-di-tert-butyl-4-methylphenol (Aldrich). The reaction mixture wasstirred at reflux for 21 h. The resulting mixture was allowed to cool toroom temperature and concentrated in vacuum. Purification by silica gelchromatography (1% MeOH/CH₂Cl₂) provided the title compound as a whiteamorphous solid. MS (ESI, pos. ion) m/z: 394 (M+1).

EXAMPLE 200

4-[6-(2-Amino-benzothiazol-4-yloxy)-pyrimidin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester. A mixture of4-(6-iodo-pyrimidin-4-yloxy)-benzothiazol-2-ylamine, (Example 129(b)),(200 mg, 0.54 mmol), 1,1-dimethylethyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-[(2H)-pyridinecarboxylate(200 mg, 0.65 mmol, prepared according Eastwood, P. R. Tetrahedron Lett.2000, 41, 3705-3708), PdCl₂(PPh₃)₂ (38 mg, 0.050 mmol, Aldrich), andNa₂CO₃ (86 mg, 0.81 mmol) in DME/EtOH/H₂O (2:1:2, 2.0 mL) was stirredand heated by microwave synthesizer at 120° C. for 15 min. The reactionmixture was concentrated in vacuum to dryness. Purification by silicagel chromatography (gradient: 0% to 5.0% MeOH/CH₂Cl₂) provided the titlecompound as a light-yellow solid. Mp: 188° C. (decomp.). MS (ESI, pos.ion) m/z: 426 (M+1).

EXAMPLE 201

4-[6-(2-Acetylamino-benzothiazol-4-yloxy)-pyrimidin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester.4-[6-(2-Amino-benzothiazol-4-yloxy)-pyrimidin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester, (Example 200), (110 mg, 0.26 mmol) was dissolvedin toluene (1.0 mL) and treated with acetic anhydride (100 μL, 1.0 mmol,Aldrich) at room temperature. The reaction mixture was stirred at 90° C.for 30 min. The resulting mixture was allowed to cool to roomtemperature and the solvents were removed in vacuum. The residue waspurified by silica gel chromatography (gradient: 0% to 4.0% MeOH/CH₂Cl₂)to provide the title compound as a light-yellow foam. MS (ESI, pos. ion)m/z: 468 (M+1), 466 (M−1).

EXAMPLE 202

(a)N-{4-[6-(2-Formyl-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide.To a suspension ofN-{4-[6-(4-trifluoromethyl-2-vinyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide,(Example 141), (120 mg, 0.25 mmol) in acetone (5.0 mL) was added water(0.5 mL), N-methylmorpholine (44 mg, 0.38 mmol, Aldrich), and OSO₄ (160μL, 0.02 mmol, 4 wt. % in water, Aldrich). The mixture was stirred atroom temperature for 20 h then treated with a solution of NaIO₄ (160 mg,0.75 mmol, Aldrich) in water (1.5 mL). The reaction mixture was stirredfor 3 h and extracted with CH₂Cl₂ and EtOAc. The combined extracts werewashed with 0.5 M Na₂S₂O₃ and brine, dried over Na₂SO₄, filtered andconcentrated in vacuum. Purification by silica gel chromatography(gradient 0% to 4.0% MeOH/CH₂Cl₂) provided the title compound as ayellow foam. MS (ESI, pos. ion) m/z: 459 (M+1), 457 (M−1).

(b)N-{4-[6-(2-Hydroxymethyl-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide.To a solution ofN-{4-[6-(2-formyl-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide(83 mg, 0.18 mmol) in MeOH (2.0 mL) at 0° C. was added NaBH4 (10 mg,0.27 mmol, Aldrich) and the reaction mixture was stirred for 1 h. Thereaction mixture was treated with water and extracted with CH₂Cl₂ andEtOAc. The combined extracts were washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuum. Purification by silica gelchromatography twice (gradient 0% to 4.0% MeOH/CH₂Cl₂ and then 1:1hexanes/EtOAc) provided the title compound as a white amorphous solid.MS (ESI, pos. ion) m/z: 461 (M+1), 459 (M−1).

EXAMPLE 203

4-[6-(4-Trifluoromethyl-piperidin-1-yl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine.To a solution of 4-(6-chloro-pyrimidin-4-yloxy)-benzothiazol-2-ylamine,(Example 133(a)), (300 mg, 1.1 mmol) in dry DMF (3.0 mL) stirred at roomtemperature was added K₂CO₃ (590 mg, 4.3 mmol) and4-(trifluoromethyl)piperidine hydrochloride (410 mg, 2.1 mmol, MatrixScientific). The reaction mixture was stirred at 80° C. for 4 h. Theresulting mixture was allowed to cool to room temperature and treatedwith water (20 mL). The resulting precipitate was collected byfiltration, washed with water (2×), MeOH (1×), and EtOAc (3×), thendried in vacuum. The title compound was obtained as a white amorphoussolid. MS (ESI, pos. ion) m/z: 396 (M+1). Anal. Calcd for C₁₇H₁₆F₃N₅OS:C, 51.64; H, 4.08; N, 17.71; F, 14.41. Found: C, 51.62; H, 4.09; N,17.61; F, 14.33.

ADDITIONAL EXAMPLES

Following the procedure described above for Example 203, or with slightmodifications thereof, the following examples were prepared:

MS (ESI, pos. ion) Melting Example Structure m/z Point ° C. 204

332 (M + 1) Amorphous solid 205

404 (M + 1) 256-257 206

446 (M + 1) 208 (decomp.) 207

390 (M + 1) 230-232 208

432 (M + 1) 236-238 209

371 (M + 1) 214 210

413 (M + 1) 264-265 211

474 (M + 1) 247 212

516 (M + 1) 208-209 213

397.2 (M + 1) 101.9-102.0 214

425.4 (M + 1) 245.5-252.7 215

447.1 (M + 1) 292.0-292.3 216

515 (M + 1) 236.1-238.0 217

515 (M + 1) 254.7-255.0 218

476 (M + 1) 270.5-271.0 219

471.2 (M + 1) 230.8-233.4 220

405.2 (M + 1) 256.6-258.9 221

461 (M + 1) 217-218 222

475 (M + 1) 132-135

EXAMPLE 223

4-(2-Bromo-phenoxy)-6-(4-trifluoromethyl-phenyl)-pyrimidine. To asolution of 2-bromophenol (2.595 g, 15 mmol, Aldrich) in anhydrous DMF(20 mL) was added NaH (0.68 g, 17 mmol, 60% suspension in mineral oil,Aldrich) in small portions with stirring at room temperature. Thereaction mixture was stirred for 0.5 h at room temperature and4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), MethodA), (2.586 g, 10 mmol) was added in one portion. The reaction mixturewas stirred for 18 h at room temperature and most of the solvent wasremoved in vacuo. The residue was dissolved in EtOAc, washed with 1NNaOH (2×) and H₂O, dried over Na₂SO₄, filtered and concentrated invacuum. The residue was recrystallized from EtOAc/hexane to give 3.21 g(81%) of the title compound. MS (ESI, pos. ion) m/z: 397 (M+1).

ADDITIONAL EXAMPLES

Following the procedures described above for Example 223, or with slightmodifications thereof, the following examples were prepared:

MS (ESI, pos. ion) Melting Example Structure m/z Point ° C. 224

368 (M + 1) 156.8-159.6 225

368.4 (M + 1) 166.5-167.9 226

368.3 (M + 1) 144.8-148.9 227

367.2 (M + 1) 152.1-153.4 228

367.2 (M + 1)  181-182.5 229

368.4 (M + 1) 209-210 230

400.3 (M + 1) 171.1-172.5 231

368.4 (M + 1) 183-185 232

388 (M + 1) 158-159 233

368 (M + 1) 159-161 234

385 (M + 1) Amorphous solid 235

368 (M + 1) 165-166 236

374 (M + 1) 166-169 237

432 (M + 1) 132-134 238

417 (M + 1) 140-143 239

426 (M + 1) 145-147 240

437 (M + 1) 194-197 241

352 (M + 1) Amorphous solid 242

383 (M + 1) Amorphous solid 243

333 (M + 1) Amorphous solid

EXAMPLE 244

(a)4-[6-Phenyl-5-(4-trifluoromethyl-phenyl)-pyridazin-3-yloxy]-benzothiazol-2-ylamine.A mixture of 6-chloro-3,4-bis-(4-trifluoromethyl-phenyl)-pyridazine,(Example 13(e)), (399, 1.2 mmol), 2-amino-4-hydroxybenzothiazole (200mg, 1.2 mmol, Astatech) and K₂CO₃ (225 mg, 1.6 mmol) in DMF (5 mL) washeated at 80° C. for 24 h. The reaction mixture was allowed to cool toroom temperature, diluted with H₂O and extracted with EtOAc (3×). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuum. The residue was dissolved in MeOH, evaporatedonto SiO₂ and purified by flash silica gel chromatography withEtOAc/hexane (0:1→2:3) as eluant to give of the title compound as awhite amorphous solid. MS (ESI, pos ion.) m/z: 465 (M+1).

(b)N-{4-[6-Phenyl-5-(4-trifluoromethyl-phenyl)-pyridazin-3-yloxy]-benzothiazol-2-yl}-acetamide.A mixture of4-[6-phenyl-5-(4-trifluoromethyl-phenyl)-pyridazin-3-yloxy]-benzothiazol-2-ylamine(142 mg, 0.3 mmol) and acetic anhydride (0.6 mL, 6.3 mmol, Aldrich) in 3mL toluene was heated at 75° C. for 4 h. The reaction was allowed tocool to room temperature and the precipitate was filtered, washed withtoluene and dried in vacuum to give the title compound as a whiteamorphous solid. Mp:>250° C. MS (ESI, pos ion.) m/z: 507 (M+1).Capsaicin-Induced Ca2+ Influx in Primary Dorsal Root Ganglion NeuronsEmbryonic 19 day old (E19) dorsal root ganglia (DRG) were dissected fromtimed-pregnant, terminally anesthetized Sprague-Dawley rats (CharlesRiver, Wilmington, Mass.) and collected in ice-cold L-15 media (LifeTechnologies, Grand Island, N.Y.) containing 5% heat inactivated horseserum (Life Technologies). The DRG were then dissociated into singlecell suspension using a papain dissociation system (WorthingtonBiochemical Corp., Freehold, N.J.). The dissociated cells were pelletedat 200×g for 5 min and re-suspended in EBSS containing 1 mg/ml ovomucoidinhibitor, 1 mg/ml ovalbumin and 0.005% DNase. Cell suspension wascentrifuged through a gradient solution containing 10 mg/ml ovomucoidinhibitor, 10 mg/ml ovalbumin at 200×g for 6 min to remove cell debris;and filtered through a 88-μm nylon mesh (Fisher Scientific, Pittsburgh,Pa.) to remove any clumps. Cell number was determined with ahemocytometer and cells were seeded into poly-ornithine 100 μg/ml(Sigma) and mouse laminin 1 μg/ml (Life Technologies)-coated 96-wellplates at 10×10³ cells/well in complete medium. The complete mediumconsists of minimal essential medium (MEM) and Ham's F12, 1:1,penicillin (100 U/ml), and streptomycin (100 μg/ml), and nerve growthfactor (10 ng/ml), 10% heat inactivated horse serum (Life Technologies).The cultures were kept at 37° C., 5% CO₂ and 100% humidity. Forcontrolling the growth of non-neuronal cells, 5-fluoro-2′-deoxyuridine(75 μM) and uridine (180 μM) were included in the medium. Activation ofVR1 is achieved in these cellular assays using either a capsaicinstimulus (ranging from 0.01-101M) or by an acid stimulus (addition of 30mM Hepes/Mes buffered at pH 4.1). Compounds are also tested in an assayformat to evaluate their agonist properties at VR1.Capsaicin Antagonist Assay: E-19 DRG cells at 5 days in culture areincubated with serial concentrations of VR1 antagonists, in HBSS (Hanksbuffered saline solution supplemented with BSA 0.1 mg/ml and 1 mM Hepesat pH 7.4) for 15 min, 37° C. Cells are then challenged with a VR1agonist, capsaicin 200 nM, in activation buffer containing 0.1 mg/mlBSA, 15 mM Hepes, pH 7.4, and 10 μCi/ml ⁴⁵Ca²⁺ (Amersham) in Ham's F12for 2 min at 37° C.Acid Antagonist Assay: Compounds are pre-incubated with E-19 DRG cellsfor 2 minutes prior to addition of Calcium-45 in 30 mM Hepes/Mes buffer(Final Assay pH 5) and then left for an additional 2 minutes prior tocompound washout. Final 45Ca (Amersham CES3-2 mCi) at 10 μCi/mL.Agonist Assay: Compounds are incubated with E-19 DRG cells for 2 minutesin the presence of Calcium-45 prior to compound washout. Final ⁴⁵Ca²⁺(Amersham CES3-2mCi) at 10 μCi/mL.Compound Washout and Analysis: Assay plates are washed using an ELX405plate washer (Bio-Tek Instruments Inc.) immediately after functionalassay. Wash 3× with PBS Mg2+/Ca2+ free, 0.1 mg/mL BSA. Aspirate betweenwashes. Read plates using a MicroBeta Jet (Wallac Inc.). Compoundactivity is then calculated using appropriate computational algorithms.⁴⁵Calcium²⁺ Assay ProtocolCompounds may be assayed using Chinese Hamster Ovary cell lines stablyexpressing either human VR1 or rat VR1 under a CMV promoter. Cells canbe cultured in Growth Medium, routinely passaged at 70% confluency usingtrypsin and plated in the assay plate 24 hours prior to compoundevaluation.Possible Growth Medium:

-   -   DMEM, high glucose (Gibco 11965-084).    -   10% Dialyzed serum (Hyclone SH30079.03).    -   1× Non-Essential Amino Acids (Gibco 11140-050).    -   1× Glutamine-Pen-Strep (Gibco 10378-016).    -   Geneticin, 450 μg/mL (Gibco 10131-035).        Compounds can be diluted in 100% DMSO and tested for activity        over several log units of concentration [40 μM-2 μM]. Compounds        may be further diluted in HBSS buffer (pH 7.4) 0.1 mg/mL BSA,        prior to evaluation. Final DMSO concentration in assay would be        0.5%. Each assay plate can be controlled with a buffer only and        a known antagonist compound (either capsazepine or one of the        described VR1 antagonists).

Activation of VR1 can be achieved in these cellular assays using eithera capsaicin stimulus (ranging from 0.1-1 μM) or by an acid stimulus(addition of 30 mM Hepes/Mes buffered at pH 4.1). Compounds may alsotested in an assay format to evaluate their agonist properties at VR1.

Capsaicin Antagonist Assay: Compounds may be pre-incubated with cells(expressing either human or rat VR1) for 2 minutes prior to addition ofCalcium-45 and Capsaicin and then left for an additional 2 minutes priorto compound 20 washout. Capsaicin (0.5 nM) can be added in HAM's F12,0.1 mg/mL BSA, 15 mM Hepes at pH 7.4. Final ⁴⁵Ca (Amersham CES3-2 mCi)at 10 μCi/mL.Acid Antagonist Assay: Compounds can be pre-incubated with cells(expressing either human or rat VR1) for 2 minutes prior to addition ofCalcium-45 in 30 mM Hepes/Mes buffer (Final Assay pH 5) and then leftfor an additional 2 minutes prior to compound washout. Final ⁴⁵Ca(Amersham CES3-2mCi) at 10 μCi/mL. Agonist Assay: Compounds can beincubated with cells (expressing either human or rat VR1) for 2 minutesin the presence of Calcium-45 prior to compound washout. Final ⁴⁵Ca(Amersham CES3-2mCi) at 10 μCi/mL.Compound Washout and Analysis: Assay plates can be washed using anELX405 plate washer (Bio-Tek Instruments Inc.) immediately afterfunctional assay. One can wash 3× with PBS Mg2⁺/Ca²⁺ free, 0.1 mg/mLBSA, aspirating between washes. Plates may be read using a MicroBeta Jet(Wallac Inc.). Compound activity may then calculated using appropriatecomputational algorithms.

Useful nucleic acid sequences and proteins may be found in U.S. Pat.Nos. 6,335,180, 6,406,908 and 6,239,267, herein incorporated byreference in their entirety.

For the treatment of vanilloid-receptor-diseases, such as acute,inflammatory and neuropathic pain, dental pain, general headache,migraine, cluster headache, mixed-vascular and non-vascular syndromes,tension headache, general inflammation, arthritis, rheumatic diseases,osteoarthritis, inflammatory bowel disorders, inflammatory eyedisorders, inflammatory or unstable bladder disorders, psoriasis, skincomplaints with inflammatory components, chronic inflammatoryconditions, inflammatory pain and associated hyperalgesia and allodynia,neuropathic pain and associated hyperalgesia and allodynia, diabeticneuropathy pain, causalgia, sympathetically maintained pain,deafferentation syndromes, asthma, epithelial tissue damage ordysfunction, herpes simplex, disturbances of visceral motility atrespiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritus, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders, the compounds of the present invention may be administeredorally, parentally, by inhalation spray, rectally, or topically indosage unit formulations containing conventional pharmaceuticallyacceptable carriers, adjuvants, and vehicles. The term parenteral asused herein includes, subcutaneous, intravenous, intramuscular,intrastemal, infusion techniques or intraperitoneally.

Treatment of diseases and disorders herein is intended to also includethe prophylactic administration of a compound of the invention, apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman) believed to be in need of preventative treatment, such as, forexample, pain, inflammation and the like.

The dosage regimen for treating vanilloid-receptor-mediated diseases,cancer, and/or hyperglycemia with the compounds of this invention and/orcompositions of this invention is based on a variety of factors,including the type of disease, the age, weight, sex, medical conditionof the patient, the severity of the condition, the route ofadministration, and the particular compound employed. Thus, the dosageregimen may vary widely, but can be determined routinely using standardmethods. Dosage levels of the order from about 0.01 mg to 30 mg perkilogram of body weight per day, preferably from about 0.1 mg to 10mg/kg, more preferably from about 0.25 mg to 1 mg/kg are useful for allmethods of use disclosed herein.

The pharmaceutically active compounds of this invention can be processedin accordance with conventional methods of pharmacy to produce medicinalagents for administration to patients, including humans and othermammals.

For oral administration, the pharmaceutical composition may be in theform of, for example, a capsule, a tablet, a suspension, or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a given amount of the active ingredient. For example,these may contain an amount of active ingredient from about 1 to 2000mg, preferably from about 1 to 500 mg, more preferably from about 5 to150 mg. A suitable daily dose for a human or other mammal may varywidely depending on the condition of the patient and other factors, but,once again, can be determined using routine methods.

The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water.The daily parenteral dosage regimen will be from about 0.1 to about 30mg/kg of total body weight, preferably from about 0.1 to about 10 mg/kg,and more preferably from about 0.25 mg to 1 mg/kg.

Injectable preparations, such as sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known areusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable non-irritating excipient such as cocoabutter and polyethylene glycols that are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

A suitable topical dose of active ingredient of a compound of theinvention is 0.1 mg to 150 mg administered one to four, preferably oneor two times daily. For topical administration, the active ingredientmay comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight ofthe formulation, although it may comprise as much as 10% w/w, butpreferably not more than 5% w/w, and more preferably from 0.1% to 1% ofthe formulation.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin(e.g., liniments, lotions, ointments, creams, or pastes) and dropssuitable for administration to the eye, ear, or nose.

For administration, the compounds of this invention are ordinarilycombined with one or more adjuvants appropriate for the indicated routeof administration. The compounds may be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, stearic acid, talc,magnesium stearate, magnesium oxide, sodium and calcium salts ofphosphoric and sulfuric acids, acacia, gelatin, sodium alginate,polyvinyl-pyrrolidine, and/or polyvinyl alcohol, and tableted orencapsulated for conventional administration. Alternatively, thecompounds of this invention may be dissolved in saline, water,polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil,cottonseed oil, sesame oil, tragacanth gum, and/or various buffers.Other adjuvants and modes of administration are well known in thepharmaceutical art. The carrier or diluent may include time delaymaterial, such as glyceryl monostearate or glyceryl distearate alone orwith a wax, or other materials well known in the art.

The pharmaceutical compositions may be made up in a solid form(including granules, powders or suppositories) or in a liquid form(e.g., solutions, suspensions, or emulsions). The pharmaceuticalcompositions may be subjected to conventional pharmaceutical operationssuch as sterilization and/or may contain conventional adjuvants, such aspreservatives, stabilizers, wetting agents, emulsifiers, buffers etc.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose, lactose, or starch. Such dosage forms may also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting, sweetening,flavoring, and perfuming agents.

Compounds of the present invention can possess one or more asymmetriccarbon atoms and are thus capable of existing in the form of opticalisomers as well as in the form of racemic or non-racemic mixturesthereof. The optical isomers can be obtained by resolution of theracemic mixtures according to conventional processes, e.g., by formationof diastereoisomeric salts, by treatment with an optically active acidor base. Examples of appropriate acids are tartaric, diacetyltartaric,dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and thenseparation of the mixture of diastereoisomers by crystallizationfollowed by liberation of the optically active bases from these salts. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column optimally chosen to maximize theseparation of the enantiomers. Still another available method involvessynthesis of covalent diastereoisomeric molecules by reacting compoundsof the invention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of theinvention can likewise be obtained by using active starting materials.These isomers may be in the form of a free acid, a free base, an esteror a salt.

Likewise, the compounds of this invention may exist as isomers, that iscompounds of the same molecular formula but in which the atoms, relativeto one another, are arranged differently. In particular, the alkylenesubstituents of the compounds of this invention, are normally andpreferably arranged and inserted into the molecules as indicated in thedefinitions for each of these groups, being read from left to right.However, in certain cases, one skilled in the art will appreciate thatit is possible to prepare compounds of this invention in which thesesubstituents are reversed in orientation relative to the other atoms inthe molecule. That is, the substituent to be inserted may be the same asthat noted above except that it is inserted into the molecule in thereverse orientation. One skilled in the art will appreciate that theseisomeric forms of the compounds of this invention are to be construed asencompassed within the scope of the present invention.

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. The salts include, but are notlimited to, the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methansulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 2-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate, andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids that may be employed to from pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulfuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Otherexamples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases.

Also encompassed in the scope of the present invention arepharmaceutically acceptable esters of a carboxylic acid or hydroxylcontaining group, including a metabolically labile ester or a prodrugform of a compound of this invention. A metabolically labile ester isone which may produce, for example, an increase in blood levels andprolong the efficacy of the corresponding non-esterified form of thecompound. A prodrug form is one which is not in an active form of themolecule as administered but which becomes therapeutically active aftersome in vivo activity or biotransformation, such as metabolism, forexample, enzymatic or hydrolytic cleavage. For a general discussion ofprodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examplesof a masked carboxylate anion include a variety of esters, such as alkyl(for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl),aralkyl (for example, benzyl, p-methoxybenzyl), andalkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have beenmasked as arylcarbonyloxymethyl substituted derivatives which arecleaved by esterases in vivo releasing the free drug and formaldehyde(Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidicNH group, such as imidazole, imide, indole and the like, have beenmasked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs,Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.EP 039,051 (Sloan and Little, Apr. 11, 1981) discloses Mannich-basehydroxamic acid prodrugs, their preparation and use. Esters of acompound of this invention, may include, for example, the methyl, ethyl,propyl, and butyl esters, as well as other suitable esters formedbetween an acidic moiety and a hydroxyl containing moiety. Metabolicallylabile esters, may include, for example, methoxymethyl, ethoxymethyl,iso-propoxymethyl, α-methoxyethyl, groups such asα-((C₁-C₄)alkyloxy)ethyl, for example, methoxyethyl, ethoxyethyl,propoxyethyl, iso-propoxyethyl, etc.; 2-oxo-1,3-dioxolen-4-ylmethylgroups, such as 5-methyl-2-oxo-1,3,dioxolen-4-ylmethyl, etc.; C₁-C₃alkylthiomethyl groups, for example, methylthiomethyl, ethylthiomethyl,isopropylthiomethyl, etc.; acyloxymethyl groups, for example,pivaloyloxymethyl, α-acetoxymethyl, etc.; ethoxycarbonyl-1-methyl; orα-acyloxy-α-substituted methyl groups, for example α-acetoxyethyl.

Further, the compounds of the invention may exist as crystalline solidswhich can be crystallized from common solvents such as ethanol,N,N-dimethyl-formamide, water, or the like. Thus, crystalline forms ofthe compounds of the invention may exist as polymorphs, solvates and/orhydrates of the parent compounds or their pharmaceutically acceptablesalts. All of such forms likewise are to be construed as falling withinthe scope of the invention.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more compounds of the invention or other agents. Whenadministered as a combination, the therapeutic agents can be formulatedas separate compositions that are given at the same time or differenttimes, or the therapeutic agents can be given as a single composition.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. A compound having the structure:

or any pharmaceutically-acceptable salt thereof, wherein: J is O or S; nis independently, at each instance, 0, 1 or
 2. R¹ is

or R¹ is R^(b) substituted by 1, 2 or 3 substituents independentlyselected from R^(f), R^(g), halo, nitro, cyano, —OR^(e), —OR^(g),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆ alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and R^(b) is additionally substituted by 0, 1 or 2groups independently selected from R^(c); or R¹ is phenyl that isvicinally fused with a saturated or unsaturated 3-, 4- or 5-atom bridgecontaining 0, 1, 2 or 3 atoms selected from O, N and S with theremaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2, wherein the heterocycle and bridge aresubstituted by 0, 1, 2 or 3 substituents independently selected from R⁵;R² is, independently, in each instance, R¹⁴, halo, C₁₋₈alkyl substitutedby 0, 1 or 2 substituents selected from R¹⁴, halo, —(CH₂)_(n)phenylsubstituted by 0, 1, 2 or 3 substituents independently selected from R¹⁴and halo, or a saturated or unsaturated 5- or 6-membered ringheterocycle containing 1, 2 or 3 heteroatoms independently selected fromN, O and S, wherein no more than 2 of the ring members are O or S,wherein the heterocycle is optionally fused with a phenyl ring, and theheterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3substituents independently selected from R¹⁴ and halo; or R² is —OR⁴ or—N(R^(a))R⁴; R³ is, independently, in each instance, H, halo, —NH₂,—NHC₁₋₃alkyl, —N(C₁₋₃alkyl)C₁₋₃alkyl, or C₁₋₃alkyl; R⁴ is independentlyat each instance

R⁴ is independently at each instance a saturated or unsaturated 5- or6-membered ring heterocycle containing 1, 2 or 3 atoms selected from O,N and S that is optionally vicinally fused with a saturated orunsaturated 3-, 4- or 5-atom bridge containing 0, 1, 2 or 3 atomsselected from O, N and S with the remaining atoms being carbon, so longas the combination of O and S atoms is not greater than 2, wherein theheterocycle and bridge are substituted by 0, 1, 2 or 3 substituentsindependently selected from R^(e), C₁₋₄haloalkyl, halo, cyano, oxo,thioxo, —OR^(f), —S(═O)_(n)R^(e), —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —OC₁₋₆alkylC(═O)OR^(e),—NR^(a)R^(f), —NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(e), —C(═O)OR^(f), —OC(═O)R^(e),—C(═O)NR^(a)R^(f) and —NR^(a)C(═O)R^(e); or R⁴ is independently at eachinstance naphthyl substituted by 1, 2 or 3 substituents independentlyselected from C₁₋₄haloalkyl, halo, nitro, cyano, —S(═O)_(n)R^(e),—OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—OC₁₋₆alklC(═O)OR^(e), —NR^(a)C₁₋₄haloalkyl,—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(e),—C(═O)OR^(f), —OC(═O)R^(e) and —C(═O)NR^(a)R^(f); but in no instance isR⁴-phenyl-(C₁₋₈alkyl), -phenyl-O—(C₁₋₆alkyl), -phenyl-NR^(a)R^(a) or-phenyl-N(R^(a))C(═O)(C₁₋₈alkyl); R⁵ is independently, at each instance,R^(f), R^(h), halo, nitro, cyano, —OR^(f), —OR^(h),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(h),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —OC(═O)R^(e), —C(═O)NR^(a)R^(f),—C(═O)NR^(a)R^(h), —NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(h),—NR^(f)C(═O)NR^(a)R^(f), —NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f),—C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f),—NR^(a)S(═O)₂R^(e), —OS(═O)₂R^(e), —OC(═O)NR^(a)R^(f), —OR^(h),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —NR^(a)R^(h),—NR^(f)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(h)C₂₋₆alkylOR^(f), —NR^(f)C₂₋₆alkylOR^(h), —CO₂R^(h), —OC(═O)R^(h),—C(═O)R^(h), —C(═O)NR^(a)R^(h), —NR^(f)C(═O)R^(h), —NR^(h)C(═O)R^(f),—NR^(h)C(═O)NR^(a)R^(f), —NR^(f)C(═O)NR^(a)R^(h), —NR^(h)CO₂R^(e),—NR^(f)CO₂R^(h), —C₁₋₈alkylOR^(h), —C₁₋₆alkylNR^(a)R^(h),—S(═O)_(n)R^(h), —S(═O)₂NR^(a)R^(h), —NR^(a)S(═O)₂R^(h),—NR^(h)S(═O)₂R^(e), —OS(═O)₂R^(h) or —OC(═O)NR^(a)R^(h); R⁶ isindependently, at each instance, H, C₁₋₅alkyl, C₁₋₄haloalkyl, halo,nitro —OR^(e), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a) or—NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a),—S(C₁₋₆alkyl), a phenyl ring substituted with 1, 2, or 3 substituentsindependently selected from R¹⁴ and halo; or R⁶ is a saturated orunsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atomsselected from O, N and S substituted with 0, 1, 2, or 3 substituentsindependently selected from R¹⁴ and halo; R⁷ is independently, at eachinstance, H, C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, —OC₁₋₆alkyl,—OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —NR^(a)R^(a),—NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a) or—S(C₁₋₆alkyl); or R⁷ is a saturated or unsaturated 4- or 5-membered ringheterocycle containing a single nitrogen atom, wherein the ring issubstituted with 0, 1 or 2 substituents independently selected fromhalo, C₁₋₂haloalkyl and C₁₋₃alkyl; R⁸ is independently, at eachinstance, H, C₁₋₅alkyl, C₁₋₄haloalkyl, halo, nitro, —OC₁₋₆alkyl,—OC₁₋₄haloalkyl, —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—NR^(a)R^(a), —NR^(a)C₁₋₄haloalkyl, —NR^(a)C₂₋₆alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), —C₁₋₈alkylOR^(a), —C₁₋₆alkylNR^(a)R^(a),—S(C₁₋₆alkyl), a phenyl ring substituted with 1, 2, or 3 substituentsindependently selected from R¹⁴ and halo, or R⁸ is a saturated orunsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atomsselected from O, N and S substituted with 0, 1, 2, or 3 substituentsindependently selected from R¹⁴ and halo; R⁹ is independently, at eachinstance, R^(f), R^(h), halo, nitro, cyano, —OR^(f), —OR^(h),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(h),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —OC(═O)R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f),—C(═O)NR^(a)R^(h), —NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(h),—NR^(f)C(═O)NR^(a)R^(f), —NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f),—C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f),—NR^(a)S(═O)₂R^(e), —OS(═O)₂R^(e), —OC(═O)NR^(a)R^(f), —OR^(h),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —NR^(a)R^(h),—NR^(f)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(h)C₂₋₆alkylOR^(f), —NR^(f)C₂₋₆alkylOR^(h), —CO₂R^(h), —OC(═O)R^(h),—C(═O)R^(h), —C(═O)NR^(a)R^(h), —NR^(f)C(═O)R^(h), —NR^(h)C(═O)R^(f),—NR^(h)C(═O)NR^(a)R^(f), —NR^(f)C(═O)NR^(a)R^(h), —NR^(h)CO₂R^(e),—NR^(f)CO₂R^(h), —C₁₋₈alkylOR^(h), —C₁₋₆alkylNR^(a)R^(h),—S(═O)_(n)R^(h), —S(═O)₂NR^(a)R^(h), —NR^(a)S(═O)₂R^(h),—NR^(h)S(═O)₂R^(e), —OS(═O)₂R^(h) or —OC(═O)NR^(a)R^(h); or R⁹ is asaturated or unsaturated 4- or 5-membered ring heterocycle containing asingle nitrogen atom, wherein the ring is substituted with 0, 1 or 2substituents independently selected from halo, C₁₋₂haloalkyl andC₁₋₃alkyl; wherein at least one of R⁵, R⁶, R⁷, R⁸ and R⁹ is R^(e),R^(h), halo, nitro, cyano, —OR^(h), —NR^(a)R^(f), —NR^(a)R^(h),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —OC(═O)R^(e), —C(═O)NR^(a)R^(f),—C(═O)NR^(a)R^(h), —NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(h),—NR^(f)C(═O)NR^(a)R^(f), —NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f),—C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f),—NR^(a)S(═O)₂R^(e), —OS(═O)₂R^(e), —OC(═O)NR^(a)R^(f), —OR^(h),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —NR^(a)R^(h),—NR^(f)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(h)C₂₋₆alkylOR^(f), —NR^(f)C₂₋₆alkylOR^(h), —CO₂R^(h), —OC(═O)R^(h),—C(═O)R^(h), —C(═O)NR^(a)R^(h), —NR^(f)C(═O)R^(h), —NR^(h)C(═O)R^(f),—NR^(h)C(═O)NR^(a)R^(f), —NR^(f)C(═O)NR^(a)R^(h), —NR^(h)CO₂R^(e),—NR^(f)CO₂R^(h), —C₁₋₈alkylOR^(h), —C₁₋₆alkylNR^(a)R^(h),—S(═O)_(n)R^(h), —S(═O)₂NR^(a)R^(h), —NR^(a)S(═O)₂R^(h),—NR^(h)S(═O)₂R^(e), —OS(═O)₂R^(h), —OC(═O)NR^(a)R^(h), or —OC₁₋₈alkylsubstituted by 1, 2 or 3 substituents independently selected from R^(f),R^(h), halo, nitro, cyano, —OR^(f), —OR^(h), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(h),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —OC(═O)R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f),—C(═O)NR^(a)R^(h), —NR^(f)C(O)R^(e), —NR^(f)C(═O)R^(h),—NR^(f)C(═O)NR^(a)R^(f), —NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f),—C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f),—NR^(a)S(═O)₂R^(e), —OS(═O)₂R^(e), —OC(═O)NR^(a)R^(f), —OR^(h),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —NR^(a)R^(h),—NR^(f)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(h)C₂₋₆alkylOR^(f), —NR^(f)C₂₋₆alkylOR^(h), —CO₂R^(h), —OC(═O)R^(h),—C(═O)R^(h), —C(═O)NR^(a)R^(h), —NR^(f)C(═O)R^(h), —NR^(h)C(═O)R^(f),—NR^(h)C(═O)NR^(a)R^(f), —NR^(f)C(═O)NR^(a)R^(h), —NR^(h)CO₂R^(e),—NR^(f)CO₂R^(h), —C₁₋₈alkylOR^(h), —C₁₋₆akylNR^(a)R^(h),—S(═O)_(n)R^(h), —S(═O)₂NR^(a)R^(h), —NR^(a)S(═O)₂R^(h),—NR^(h)S(═O)₂R^(e), —OS(═O)₂R^(h) and —OC(═O)NR^(a)R^(h); R¹⁰ isindependently, at each instance, selected from H, C₁₋₅alkyl,C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(h)C₂₋₆alkylOR^(f) and —NR^(a)C₂₋₆alkylOR^(h); or R¹⁰ is a saturatedor unsaturated 5-, 6- or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or11-membered bicyclic ring containing 1, 2 or 3 atoms selected from N, Oand S, wherein there are no more than 2 N atoms, wherein the ring issubstituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring issubstituted by 0, 1, 2 or 3 groups selected from R^(e), halo, cyano,nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R_(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹⁰ is C₁₋₄alkyl substituted by 0, 1, 2 or 3groups selected from C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); R¹¹ is independently, at each instance, selectedfrom H, C₁₋₈alkyl, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹¹ is a saturated or unsaturated 5-, 6- or7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclicring containing 1, 2 or 3 atoms selected from N, O and S, wherein thering is substituted by 0, 1 or 2 oxo or thioxo groups, wherein the ringis substituted by 0, 1, 2 or 3 groups selected from R^(e), halo, cyano,nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹¹ is C₁₋₄alkyl substituted by 0, 1, 2 or 3groups selected from C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹⁰ and R¹¹ together are a saturated orunsaturated 3-, 4- or 5-atom bridge containing 1, 2 or 3 atoms selectedfrom O, N and S with the remaining atoms being carbon, so long as thecombination of O and S atoms is not greater than 2, wherein the bridgeis substituted by 0, 1 or 2 substituents selected from oxo, thioxo,R^(C), R^(e), halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹⁰ and R¹¹ together are a saturated orpartially unsaturated 3-, 4- or 5-carbon bridge, wherein the bridge issubstituted by 0, 1 or 2 substituents selected from oxo, thioxo, R^(c),R^(e), halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); and when R¹⁰ and R¹¹ together form a bridge, R¹²may additionally be halo or —CF₃, R¹³ may additionally be halo or—OR^(a) or cyano or nitro, and R¹⁴ may additionally be halo; R¹² isindependently, at each instance, selected from H, C₁₋₈alkyl, cyano,nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkyl NR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹² is a saturated or unsaturated 5-, 6- or7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclicring containing 1, 2 or 3 atoms selected from N, O and S, wherein thering is substituted by 0, 1 or 2 oxo or thioxo groups, wherein the ringis substituted by 0, 1, 2 or 3 groups selected from R^(e), halo, cyano,nitro, —C(═O)R^(e), —C(═O)OR^(e), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹² is C₁₋₄alkyl substituted by 0, 1, 2 or 3groups selected from C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h), and additionally substituted by 0, 1 or 2 halogroups; or R¹¹ and R¹² together are a saturated or unsaturated 3-, 4- or5-atom bridge containing 1, 2 or 3 atoms selected from O, N and S withthe remaining atoms being carbon, so long as the combination of O and Satoms is not greater than 2, wherein the bridge is substituted by 0, 1or 2 substituents selected from oxo, thioxo, R^(c), R^(e), halo, cyano,nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); wherein when R³ is NH₂, then —R¹¹—R¹²— is not—C═C—C═N— or any substituted version thereof; or R¹¹ and R¹² togetherare a saturated or partially unsaturated 3-, 4- or 5-carbon bridge,wherein the bridge is substituted by 0, 1 or 2 substituents selectedfrom oxo, thioxo, R^(c), R^(e), halo, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); and when R¹¹ and R¹² together form a bridge, R¹⁰may additionally be halo, R¹³ may additionally be halo or —OR^(a) orcyano or nitro, and R¹⁴ may additionally be halo; R¹³ is independently,at each instance, selected from H, C₁₋₈alkyl, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹³ is a saturated or unsaturated 5-, 6- or7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclicring containing 1, 2 or 3 atoms selected from N, O and S, wherein thering is substituted by 0, 1 or 2 oxo or thioxo groups, wherein the ringis substituted by 0, 1, 2 or 3 groups selected from R^(e), halo, cyano,nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹³ is C₁₋₄alkyl substituted by 0, 1, 2 or 3groups selected from C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); R¹⁴ is independently, at each instance, selectedfrom H, C₁₋₅alkyl, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(e))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹⁴ is a saturated or unsaturated 5-, 6- or7-membered monocyclic or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclicring containing 1, 2 or 3 atoms selected from N, O and S, wherein thereare no more than 2 N atoms, wherein the ring is substituted by 0, 1 or 2oxo or thioxo groups, wherein the ring is substituted by 0, 1, 2 or 3groups selected from R^(e), halo, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(f), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); or R¹⁴ is C₁₋₄alkyl substituted by 0, 1, 2 or 3groups selected from C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(e),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a) R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), 13 N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); wherein at least one of R¹⁰, R¹¹, R¹², R¹³ andR¹⁴ is other than H; R^(a) is independently, at each instance, H,phenyl, benzyl or C₁₋₆alkyl, the phenyl, benzyl and C₁₋₆alkyl beingsubstituted by 0, 1, 2 or 3 substituents selected from halo, C₁₋₄alkyl,C₁₋₃haloalkyl, —OC₁₋₄alkyl, —NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C₁₋₄alkyl;R^(b) is a heterocycle selected from the group of thiophene, pyrrole,1,3-oxazole, 1,3-thiazol-4-yl, 1,3,4-oxadiazole, 1,3,4-thiadiazole,1,2,3-oxadiazole, 1,2,3-thiadiazole, 1H-1,2,3-triazole, isothiazole,1,2,4-oxadiazole, 1,2,4-thiadiazole, 1,2,3,4-oxatriazole,1,2,3,4-thiatriazole, 1H-1,2,3,4-tetraazole, 1,2,3,5-oxatriazole,1,2,3,5-thiatriazole, furan, imidazol-2-yl, benzimidazole,1,2,4-triazole, isoxazole, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl,thiolane, pyrrolidine, tetrahydrofuran, 4,5-dihydrothiophene,2-pyrroline, 4,5-dihydrofuran, pyridazine, pyrimidine, pyrazine,1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, pyridine,2H-3,4,5,6-tetrahydropyran, thiane, 1,2-diazaperhydroine,1,3-diazaperhydroine, piperazine, 1,3-oxazaperhydroine, morpholine,1,3-thiazaperhydroine, 1,4-thiazaperhydroine, piperidine,2H-3,4-dihydropyran, 2,3-dihydro-4H-thiin, 1,4,5,6-tetrahydropyridine,2H-5,6-dihydropyran, 2,3-dihydro-6H-thiin, 1,2,5,6-tetrahydropyridine,3,4,5,6-tetrahydropyridine, 4H-pyran, 4H-thiin, 1,4-dihydropyridine,1,4-dithiane, 1,4-dioxane, 1,4-oxathiane, 1,2-oxazolidine,1,2-thiazolidine, pyrazolidine, 1,3-oxazolidine, 1,3-thiazolidine,imidazolidine, 1,2,4-oxadiazolidine, 1,3,4-oxadiazolidine,1,2,4-thiadiazolidine, 1,3,4-thiadiazolidine, 1,2,4-triazolidine,2-imidazolin-1-yl, 2-imidazolin-2-yl, 3-imidazoline, 2-pyrazoline,4-imidazoline, 2,3-dihydroisothiazole, 4,5-dihydroisoxazole,4,5-dihydroisothiazole, 2,5-dihydroisoxazole, 2,5-dihydroisothiazole,2,3-dihydroisoxazole, 4,5-dihydrooxazole, 2,3-dihydrooxazole,2,5-dihydrooxazole, 4,5-dihydrothiazole, 2,3-dihydrothiazole,2,5-dihydrothiazole, 1,3,4-oxathiazolidine, 1,4,2-oxathiazolidine,2,3-dihydro-1H-[1,2,3]triazole, 2,5-dihydro-1H-[1,2,3]triazole,4,5-dihydro-1H-[1,2,3]triazol-1-yl, 4,5-dihydro-1H-[1,2,3]triazol-3-yl,4,5-dihydro-1H-[1,2,3]triazol-5-yl, 2,3-dihydro-1H-[1,2,4]triazole,4,5-dihydro-1H-[1,2,4]triazole, 2,3-dihydro-[1,2,4]oxadiazole,2,5-dihydro-[1,2,4]oxadiazole, 4,5-dihydro-[1,2,4]thiadiazole,2,3-dihydro-[1,2,4]thiadiazole, 2,5-dihydro-[1,2,4]thiadiazole,4,5-dihydro-[1,2,4]thiadiazole, 2,5-dihydro-[1,2,4]oxadiazole,2,3-dihydro-[1,2,4]oxadiazole, 4,5-dihydro-[1,2,4]oxadiazole,2,5-dihydro-[1,2,4]thiadiazole, 2,3-dihydro-[1,2,4]thiadiazole,4,5-dihydro-[1,2,4]thiadiazole, 2,3-dihydro-[1,3,4]oxadiazole,2,3-dihydro-[1,3,4]thiadiazole, [1,4,2]oxathiazole, [1,3,4]oxathiazole,1,3,5-triazaperhydroine, 1,2,4-triazaperhydroine,1,4,2-dithiazaperhydroine, 1,4,2-dioxazaperhydroine,1,3,5-oxadiazaperhydroine, 1,2,5-oxadiazaperhydroine,1,3,4-thiadiazaperhydroine, 1,3,5-thiadiazaperhydroine,1,2,5-thiadiazaperhydroine, 1,3,4-oxadiazaperhydroine,1,4,3-oxathiazaperhydroine, 1,4,2-oxathiazaperhydroine,1,4,5,6-tetrahydropyridazine, 1,2,3,4-tetrahydropyridazine,1,2,3,6-tetrahydropyridazine, 1,2,5,6-tetrahydropyrimidine,1,2,3,4-tetrahydropyrimidine, 1,4,5,6-tetrahydropyrimidine,1,2,3,6-tetrahydropyrazine, 1,2,3,4-tetrahydropyrazine,5,6-dihydro-4H-[1,2]oxazine, 5,6-dihydro-2H-[1,2]oxazine,3,6-dihydro-2H-[1,2]oxazine, 3,4-dihydro-2H-[1,2]oxazine,5,6-dihydro-4H-[1,2]thiazine, 5,6-dihydro-2H-[1,2]thiazine,3,6-dihydro-2H-[1,2]thiazine, 3,4-dihydro-2H-[1,2]thiazine,5,6-dihydro-2H-[1,3]oxazine, 5,6-dihydro-4H-[1,3]oxazine,3,6-dihydro-2H-[1,3]oxazine, 3,4-dihydro-2H-[1,3]oxazine,3,6-dihydro-2H-[1,4]oxazine, 3,4-dihydro-2H-[1,4]oxazine,5,6-dihydro-2H-[1,3]thiazine, 5,6-dihydro-4H-[1,3]thiazine,3,6-dihydro-2H-[1,3]thiazine, 3,4-dihydro-2H-[1,3]thiazine,3,6-dihydro-2H-[1,4]thiazine, 3,4-dihydro-2H-[1,4]thiazine,1,2,3,6-tetrahydro-[1,2,4]triazine, 1,2,3,4-tetrahydro-[1,2,4]triazine,1,2,3,4-tetrahydro-[1,3,5]triazine, 2,3,4,5-tetrahydro-[1,2,4]triazine,1,4,5,6-tetrahydro-[1,2,4]triazine, 5,6-dihydro-[1,4,2]dioxazine,5,6-dihydro-[1,4,2]dithiazine, 2,3-dihydro-[1,4,2]dioxazine,3,4-dihydro-2H-[1,3,4]oxadiazine, 3,6-dihydro-2H-[1,3,4]oxadiazine,3,4-dihydro-2H-[1,3,5]oxadiazine, 3,6-dihydro-2H-[1,3,5]oxadiazine,5,6-dihydro-2H-[1,2,5]oxadiazine, 5,6-dihydro-4H-[1,2,5]oxadiazine,3,4-dihydro-2H-[1,3,4]thiadiazine, 3,6-dihydro-2H-[1,3,4]thiadiazine,3,4-dihydro-2H-[1,3,5]thiadiazine, 3,6-dihydro-2H-[1,3,5]thiadiazine,5,6-dihydro-2H-[1,2,5]thiadiazine, 5,6-dihydro-4H-[1,2,5]thiadiazine,5,6-dihydro-2H-[1,2,3]oxadiazine, 3,6-dihydro-2H-[1,2,5]oxadiazine,5,6-dihydro-4H-[1,3,4]oxadiazine, 3,4-dihydro-2H-[1,2,5]oxadiazine,5,6-dihydro-2H-[1,2,3]thiadiazine, 3,6-dihydro-2H-[1,2,5]thiadiazine,5,6-dihydro-4H-[1,3,4]thiadiazine, 3,4-dihydro-2H-[1,2,5]thiadiazine,5,6-dihydro-[1,4,3]oxathiazine, 5,6-dihydro-[1,4,2]oxathiazine,2,3-dihydro-[1,4,3]oxathiazine, 2,3-dihydro-[1,4,2]oxathiazine,3,4-dihydropyridine, 1,2-dihydropyridine, 5,6-dihydropyridine, 2H-pyran,2H-thiin, 3,6-dihydropyridine, 2,3-dihydropyridazine,2,5-dihydropyridazine, 4,5-dihydropyridazine, 1,2-dihydropyridazine,1,4-dihydropyrimidin-1-yl, 1,4-dihydropyrimidin-4-yl,1,4-dihydropyrimidin-5-yl, 1,4-dihydropyrimidin-6-yl,2,3-dihydropyrimidine, 2,5-dihydropyrimidine, 5,6-dihydropyrimidine,3,6-dihydropyrimidine, 5,6-dihydropyrazine, 3,6-dihydropyrazine,4,5-dihydropyrazine, 1,4-dihydropyrazine, 1,4-dithiin, 1,4-dioxin,2H-1,2-oxazine, 6H-1,2-oxazine, 4H-1,2-oxazine, 2H-1,3-oxazine,4H-1,3-oxazine, 6H-1,3-oxazine, 2H-1,4-oxazine, 4H-1,4-oxazine,2H-1,3-thiazine, 2H-1,4-thiazine, 4H-1,2-thiazine, 6H-1,3-thiazine,4H-1,4-thiazine, 2H-1,2-thiazine, 6H-1,2-thiazine, 1,4-oxathiin,2H,5H-1,2,3-triazine, 1H,4H-1,2,3-triazine, 4,5-dihydro-1,2,3-triazine,1H,6H-1,2,3-triazine, 1,2-dihydro-1,2,3-triazine,2,3-dihydro-1,2,4-triazine, 3H,6H-1,2,4-triazine, 1H,6H-1,2,4-triazine,3,4-dihydro-1,2,4-triazine, 1H,4H-1,2,4-triazine,5,6-dihydro-1,2,4-triazine, 4,5-dihydro-1,2,4-triazine,2H,5H-1,2,4-triazine, 1,2-dihydro-1,2,4-triazine, 1H,4H-1,3,5-triazine,1,2-dihydro-1,3,5-triazine, 1,4,2-dithiazine, 1,4,2-dioxazine,2H-1,3,4-oxadiazine, 2H-1,3,5-oxadiazine, 6H-1,2,5-oxadiazine,4H-1,3,4-oxadiazine, 4H-1,3,5-oxadiazine, 4H-1,2,5-oxadiazine,2H-1,3,5-thiadiazine, 6H-1,2,5-thiadiazine, 4H-1,3,4-thiadiazine,4H-1,3,5-thiadiazine, 4H-1,2,5-thiadiazine, 2H-1,3,4-thiadiazine,6H-1,3,4-thiadiazine, 6H-1,3,4-oxadiazine, and 1,4,2-oxathiazine,wherein the heterocycle is optionally vicinally fused with a saturatedor unsaturated 5-, 6- or 7-membered ring containing 0, 1 or 2 atomsindependently selected from N, O and S; R^(c) is independently, in eachinstance, phenyl substituted by 0, 1 or 2 groups selected from halo,C₁₋₄alkyl, C₁₋₃haloalkyl, —OR^(a) and —NR^(a)R^(a); or R^(c) is asaturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S, wherein nomore than 2 of the ring members are O or S, wherein the heterocycle isoptionally fused with a phenyl ring, and the carbon atoms of theheterocycle are substituted by 0, 1 or 2 oxo or thioxo groups, whereinthe heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OR^(a) and—NR^(a)R^(a); R^(d) is independently in each instance hydrogen or —CH₃;R^(e) is, independently, in each instance, C₁₋₉alkyl orC₁₋₄alkyl(phenyl) wherein either is substituted by 0, 1, 2, 3 or 4substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a) —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a)—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(a),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and—NR^(a)C₂₋₆alkylOR^(a); and wherein the C₁₋₉alkyl is additionallysubstituted by 0 or 1 groups independently selected from R^(h); R^(f)is, independently, in each instance, R^(e) or H; R^(g) is,independently, in each instance, a saturated or unsaturated 5- or6-membered monocyclic ring containing 1, 2 or 3 atoms selected from N, Oand S, so long as the combination of O and S atoms is not greater than2, wherein the ring is substituted by 0 or 1 oxo or thioxo groups; andR^(h) is, independently, in each instance, phenyl or a saturated orunsaturated 5- or 6-membered monocyclic ring containing 1, 2 or 3 atomsselected from N, O and S, so long as the combination of O and S atoms isnot greater than 2, wherein the ring is substituted by 0 or 1 oxo orthioxo groups, wherein the phenyl or monocycle are substituted by 0, 1,2 or 3 substituents selected from halo, cyano, nitro, —C(═O)R^(e),—C(═O)OR^(e), —C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f),—OC(═O)R^(e), —OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —SR^(f), —S(═O)R^(e),—S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(e), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(e),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f) and —NR^(a)C₂₋₆alkylOR^(f).
 2. A compoundselected from the group of:N-[4-({5-(4-fluorophenyl)-4-[4-(trifluoromethyl)phenyl]pyridin-2-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({5-[4-(trifluoromethoxy)phenyl]-4-[4-(trifluoromethyl)phenyl]pyridin-2-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({5-bromo-4-[4-(trifluoromethyl)phenyl]pyridin-2-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;N-[4-({5-chloro-4-[4-(trifluoromethyl)phenyl]pyridin-2-yl}oxy)-1,3-benzothiazol-2-yl]acetamide;or any pharmaceutically-acceptable salts thereof.
 3. A compoundaccording to claim 1, R¹ is piperidine or pyrimidine, either onesubstituted by 1, 2 or 3 substituents independently selected from R^(f),R^(g) halo, nitro, cyano, —OR^(e), —OR^(g), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and R^(b) is additionally substituted by 0, 1 or 2groups independently selected from R^(c).
 4. A compound according toclaim 3, wherein R⁷ is —CF₃.
 5. A compound according to claim 3, whereinR⁷ is —C(CH₃)₃.
 6. A compound according to claim 1, R¹ is R^(b), whereinR^(b) substituted by 1, 2 or 3 substituents independently selected fromR^(f), R^(g), halo, nitro, cyano, —OR^(e), —OR^(g),—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(g),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and R^(b) is additionally substituted by 0, 1 or 2groups independently selected from R^(c).
 7. A compound according toclaim 1, R¹ is pyridine substituted by 1, 2 or 3 substituentsindependently selected from R^(f), R^(g), halo, nitro, cyano, —OR^(e),—OR^(g), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —NR^(a)R^(f),—NR^(a)R^(g), —NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f),naphthyl, —CO₂R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f), —C(═O)NR^(a)R^(g),—NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(g), —NR^(f)C(═O)NR^(a)R^(f),—NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f), —C₁₋₆alkylNR^(a)R^(f),—S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f), —NR^(a)S(═O)₂R^(e) and—OC(═O)NR^(a)R^(f), and R^(b) is additionally substituted by 0, 1 or 2groups independently selected from R^(c).
 8. A compound according toclaim 1, wherein R¹ is phenyl that is vicinally fused with a saturatedor unsaturated 3-, 4- or 5-atom bridge containing 0, 1, 2 or 3 atomsselected from O, N and S with the remaining atoms being carbon, so longas the combination of O and S atoms is not greater than 2, wherein theheterocycle and bridge are substituted by 0, 1, 2 or 3 substituentsindependently selected from R⁵.
 9. A compound according to claim 1,wherein R² is, independently, in each instance, R¹⁴, halo, C₁₋₈alkylsubstituted by 0, 1 or 2 substituents selected from R¹⁴, halo,—(CH₂)_(n)phenyl substituted by 0, 1, 2 or 3 substituents independentlyselected from R¹⁴ and halo, or a saturated or unsaturated 5- or6-membered ring heterocycle containing 1, 2 or 3 heteroatomsindependently selected from N, O and S, wherein no more than 2 of thering members are O or S, wherein the heterocycle is optionally fusedwith a phenyl ring, and the heterocycle or fused phenyl ring issubstituted by 0, 1, 2 or 3 substituents independently selected from R¹⁴and halo; or R² is —OR⁴ or —N(R^(a))R⁴; and R³ is H, wherein at leastone of R² and R³ is other than H.
 10. A compound according to claim 1,wherein R² is H; and R³ is halo, —NH₂, —NHC₁₋₃alkyl,—N(C₁₋₃alkyl)C₁₋₃alkyl, or C₁₋₃alkyl.
 11. A compound according to claim1, wherein R⁴ is independently at each instance

but in no instance is R⁴-phenyl-O—(C₁₋₆alkyl), -phenyl-NR^(a)R^(a) or-phenyl-N(R^(a))C(═O)(C₁₋₈alkyl).
 12. A compound according to claim 1,wherein R⁵ is H.
 13. A compound according to claim 12, wherein R¹⁰ andR¹¹ together are a saturated or unsaturated 3-, 4- or 5-atom bridgecontaining 1, 2 or 3 atoms selected from O, N and S with the remainingatoms being carbon, so long as the combination of O and S atoms is notgreater than 2, wherein the bridge is substituted by 0, 1 or 2substituents selected from oxo, thioxo, R^(c), R^(e), halo, cyano,nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(═O)OR^(h), —C(═O)NR^(a)R^(h),—C(═NR^(a))NR^(a)R^(h), —OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); and when R¹⁰ and R¹¹ together form a bridge, R¹²may additionally be halo or —CF₃, R¹³ may additionally be halo or—OR^(a) or cyano or nitro, and R¹⁴ may additionally be halo.
 14. Acompound according to claim 12, wherein R¹¹ and R¹² together are asaturated or unsaturated 3-, 4- or 5-atom bridge containing 1, 2 or 3atoms selected from O, N and S with the remaining atoms being carbon, solong as the combination of O and S atoms is not greater than 2, whereinthe bridge is substituted by 0, 1 or 2 substituents selected from oxo,thioxo, R^(c), R^(e), halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f),—C(═O)NR^(a)R^(f), —C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e),—OC(═O)NR^(a)R^(f), —OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —SR^(e), —S(═O)R^(e), —S(═O)₂R^(e),—S(═O)₂NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(f),—NR^(a)R^(f), —N(R^(a))C(═O)R^(e), —N(R^(a))C(═O)OR^(f),—N(R^(a))C(═O)NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(f),—N(R^(a))S(═O)₂R^(e), —N(R^(a))S(═O)₂NR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h),—C(═O)OR^(h), —C(═O)NR^(a)R^(h), —C(═NR^(a))NR^(a)R^(h), —OR^(h),—OC(═O)R^(h), —OC(═O)NR^(a)R^(h), —OC(═O)N(R^(a))S(═O)₂R^(h),—OC(═O)N(R^(h))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h),—SR^(h), —S(═O)R^(h), —S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h),—S(═O)₂N(R^(h))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)R^(h),—S(═O)₂N(R^(h))C(═O)OR^(f), —S(═O)₂N(R^(a))C(═O)OR^(h),—S(═O)₂N(R^(h))C(═O)NR^(a)R^(f), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(h),—NR^(a)R^(h), —N(R^(h))C(═O)R^(e), —N(R^(a))C(═O)R^(h),—N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h), —N(R^(h))C(═O)NR^(a)R^(f),—N(R^(a))C(═O)NR^(a)R^(h), —N(R^(h))C(═NR^(a))NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(h), —N(R^(h))S(═O)₂R^(e),—N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); wherein —R¹¹—R¹²— is not —C(NH₂)═C—C═N— or anysubstituted version thereof; or R¹¹ and R¹² together are a saturated orpartially unsaturated 3-, 4- or 5-carbon bridge, wherein the bridge issubstituted by 0, 1 or 2 substituents selected from oxo, thioxo, R^(c),R^(e), halo, cyano, nitro, —C(═O)R^(e), —C(═O)OR^(f), —C(═O)NR^(a)R^(f),—C(═NR^(a))NR^(a)R^(f), —OR^(f), —OC(═O)R^(e), —OC(═O)NR^(a)R^(f),—OC(═O)N(R^(a))S(═O)₂R^(e), —OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f),—SR^(e), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)R^(e), —S(═O)₂N(R^(a))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(f), —NR^(a)R^(f), —N(R^(a))C(═O)R^(e),—N(R^(a))C(═O)OR^(f), —N(R^(a))C(═O)NR^(a)R^(f),—N(R^(a))C(═NR^(a))NR^(a)R^(f), —N(R^(a))S(═O)₂R^(e),—N(R^(a))S(═O)₂NR^(a)R^(f), —NR^(a)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(h), —C(O)OR^(h), —C(═O)NR^(a)R^(h)C(═NR^(a))NR^(a)R^(h), OR^(h), —OC(═O)R^(h), —OC(═O)NR^(a)R^(h),—OC(═O)N(R^(a))S(═O)₂R^(h), —OC(═O)N(R^(h))S(═O)₂R^(e),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —SR^(h), —S(═O)R^(h),—S(═O)₂R^(h), —S(═O)₂NR^(a)R^(h), —S(═O)₂N(R^(h))C(═O)R^(e),—S(═O)₂N(R^(a))C(═O)R^(h), —S(═O)₂N(R^(h))C(═O)OR^(f),—S(═O)₂N(R^(a))C(═O)OR^(h), —S(═O)₂N(R^(h))C(═O)NR^(a)R^(f),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(h), —NR^(a)R^(h), —N(R^(h))C(═O)R^(e),—N(R^(a))C(═O)R^(h), —N(R^(h))C(═O)OR^(f), —N(R^(a))C(═O)OR^(h),—N(R^(h))C(═O)NR^(a)R^(f), —N(R^(a))C(═O)NR^(a)R^(h),—N(R^(h))C(═NR^(a))NR^(a)R^(f), —N(R^(a))C(═NR^(a))NR^(a)R^(h),—N(R^(h))S(═O)₂R^(e), —N(R^(a))S(═O)₂R^(h), —N(R^(h))S(═O)₂NR^(a)R^(f),—N(R^(a))S(═O)₂NR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(a)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylOR^(f) and—NR^(a)C₂₋₆alkylOR^(h); and when R¹¹ and R¹² together form a bridge, R¹⁰may additionally be halo, R¹³ may additionally be halo or —OR^(a) orcyano or nitro, and R]⁴ may additionally be halo.
 15. A compoundaccording to claim 1, wherein R⁴ is independently at each instance asaturated or unsaturated 5- or 6-membered ring heterocycle containing 1,2 or 3 atoms selected from O, N and S that is optionally vicinally fusedwith a saturated or unsaturated 3-, 4- or 5-atom bridge containing 0, 1,2 or 3 atoms selected from O, N and S with the remaining atoms beingcarbon, so long as the combination of 0 and S atoms is not greater than2, wherein the heterocycle and bridge are substituted by 0, 1, 2 or 3substituents independently selected from R^(e), C₁₋₄haloalkyl, halo,cyano, oxo, thioxo, —OR^(f), —S(═O)_(n)R^(e), —OC₁₋₄haloalkyl,—OC₂₋₆alkylNR^(a)R^(f), —OC₂₋₆alkylOR^(f), —OC₁₋₆alkylOR^(f),—C(═O)OR^(e), —NR^(a)R^(f), —NR^(a)C₁₋₄haloalkyl,—NR^(a)C₂₋₆alkylNR^(a)R^(f), —NR^(a)C₂₋₆alkylOR^(f), —C(═O)R^(e),—C(═O)OR^(f), —OC(═O)R^(e), —C(═O)NR^(a)R^(f) and —NR^(a)C(═O)R^(e). 16.A compound according to claim 3, wherein R⁵ is R^(f), R^(h), halo,nitro, cyano, —OR^(f), —OR^(f), —OC₂₋₆alkylNR^(a)R^(f),—OC₂₋₆alkylOR^(f), —NR^(a)R^(f), —NR^(a)R^(h),—NR^(f)C₂₋₆alkylNR^(a)R^(f), —NR^(f)C₂₋₆alkylOR^(f), naphthyl,—CO₂R^(e), —OC(═O)R^(e), —C(═O)R^(e), —C(═O)NR^(a)R^(f),—C(═O)NR^(a)R^(h), —NR^(f)C(═O)R^(e), —NR^(f)C(═O)R^(h),—NR^(f)C(═O)NR^(a)R^(f), —NR^(f)CO₂R^(e), —C₁₋₈alkylOR^(f),—C₁₋₆alkylNR^(a)R^(f), —S(═O)_(n)R^(e), —S(═O)₂NR^(a)R^(f),—NR^(a)S(═O)₂R^(e), —OS(═O)₂R^(e), —OC(═O)NR^(a)R^(f), —OR^(h),—OC₂₋₆alkylNR^(a)R^(h), —OC₂₋₆alkylOR^(h), —NR^(a)R^(h),—NR^(f)C₂₋₆alkylNR^(a)R^(h), —NR^(h)C₂₋₆alkylNR^(a)R^(f),—NR^(h)C₂₋₆alkylOR^(f), —NR^(f)C₂₋₆alkylOR^(h), —CO₂R^(h), —OC(═O)R^(h),—C(═O)R^(h), —C(═O)NR^(a)R^(h), —NR^(f)C(═O)R^(h), —NR^(h)C(═O)R^(f),—NR^(h)C(═O)NR^(a)R^(f), —NR^(f)C(═O)NR^(a)R^(h), —NR^(h)CO₂R^(e),—NR^(f)CO₂R^(h), —C₁₋₈alkylOR^(h), —C₁₋₈alkylNR^(a)R^(h),—S(═O)_(n)R^(h), —S(═O)₂NR^(a)R^(h), —NR^(a)S(═O)₂R^(h),—NR^(h)S(═O)₂R^(h), —OS(═O)₂R^(h) or —OC(═O)NR^(a)R^(h).
 17. A compoundaccording to claim 1, wherein R⁵ is R^(f) or R^(h).
 18. A pharmaceuticalcomposition comprising a compound according to claim 1 and apharmaceutically-acceptable diluent or carrier.
 19. A compound accordingto claim 1, wherein R¹ is